Anti-cytokine heterocyclic compounds

ABSTRACT

Disclosed compounds of formula (I)  
                 
which inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

APPLICATION DATA

This application claims benefit to U.S. provisional application No.60/551,445 filed Mar. 9, 2004.

1. TECHNICAL FIELD

This invention relates to compounds of formula (I)

The compounds of the invention inhibit production of cytokines involvedin inflammatory processes and are thus useful for treating diseases andpathological conditions involving inflammation such as chronicinflammatory disease. This invention also relates to processes forpreparing these compounds and to pharmaceutical compositions comprisingthese compounds.

2. BACKGROUND INFORMATION

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are importantbiological entities collectively referred to as proinflammatorycytokines which play a role in cytokine mediated diseases. These, alongwith several other related molecules, mediate the inflammatory responseassociated with the immunological recognition of infectious agents. Theinflammatory response plays an important role in limiting andcontrolling pathogenic infections.

Elevated levels of proinflammatory cytokines are also associated with anumber of diseases of autoimmunity such as toxic shock syndrome,rheumatoid arthritis, osteoarthritis, diabetes and inflammatory boweldisease (Dinarello, C. A. , et al., 1984, Rev. Infect. Disease 6:51). Inthese diseases, chronic elevation of inflammation exacerbates or causesmuch of the pathophysiology observed. For example, rheumatoid synovialtissue becomes invaded with inflammatory cells that result indestruction to cartilage and bone (Koch, A. E. , et al., 1995, J.Invest. Med. 43: 28-38). Studies suggest that inflammatory changesmediated by cytokines may be involved in endothelial cell pathogenesisincluding restenosis after percutaneous transluminal coronaryangioplasty (PTCA) (Tashiro, H., et al., 2001 Mar, Coron Artery Dis12(2):107-13). An important and accepted therapeutic approach forpotential drug intervention in these diseases is the reduction ofproinflammatory cytokines such as TNF (also referred to in its secretedcell-free form as TNFα) and IL-1β. A number of anti-cytokine therapiesare currently in clinical trials. Efficacy has been demonstrated with amonoclonal antibody directed against TNFα in a number of autoimmunediseases (Heath, P., “CDP571: An Engineered Human IgG4 Anti-TNFαAntibody” IBC Meeting on Cytokine Antagonists, Philadelphia, Pa., Apr.24-5, 1997). These include the treatment of rheumatoid arthritis,Crohn's disease and ulcerative colitis (Rankin, E. C. C., et al., 1997,British J. Rheum. 35: 334-342 and Stack, W. A. , et al., 1997, Lancet349: 521-524). The monoclonal antibody is thought to function by bindingto both soluble TNFα and to membrane bound TNF.

A soluble TNFα receptor has been engineered that interacts with TNFα.The approach is similar to that described above for the monoclonalantibodies directed against TNFα; both agents bind to soluble TNFα, thusreducing its concentration. One version of this construct, called Enbrel(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase IIIclinical trial for the treatment of rheumatoid arthritis (Brower et al.,1997, Nature Biotechnology 15: 1240). Another version of the TNFα:receptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) hasdemonstrated efficacy in various animal models of allergic lunginflammation and acute lung injury. Ro 45-2081 is a recombinant chimericmolecule constructed from the soluble 55 kDa human TNF receptor fused tothe hinge region of the heavy chain IgG1 gene and expressed ineukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S 143).

IL-1 has been implicated as an immunological effector molecule in alarge number of disease processes. IL-1 receptor antagonist (IL-1ra) hadbeen examined in human clinical trials. Efficacy has been demonstratedfor the treatment of rheumatoid arthritis (Antril, Amgen). In a phaseIII human clinical trial IL-1ra reduced the mortality rate in patientswith septic shock syndrome (Dinarello, 1995, Nutrution 11, 492).Osteoarthritis is a slow progressive disease characterized bydestruction of the articular cartilage. IL-1 is detected in synovialfluid and in the cartilage matrix of osteoarthritic joints. Antagonistsof IL-1 have been shown to diminish the degradation of cartilage matrixcomponents in a variety of experimental models of arthritis (Chevalier,1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator ofcardiovascular homeostasis, neurotransmission and immune function;recently it has been shown to have important effects in the modulationof bone remodeling. Cytokines such as IL-1 and TNF are potentstimulators of NO production. NO is an important regulatory molecule inbone with effects on cells of the osteoblast and osteoclast lineage(Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion ofbeta-cell destruction leading to insulin dependent diabetes mellitusshows dependence on IL-1. Some of this damage may be mediated throughother effectors such as prostaglandins and thromboxanes. IL-1 can effectthis process by controlling the level of both cyclooxygenase II andinducible nitric oxide synthetase expression (McDaniel et al., 1996,Proc Soc Exp Biol Med. 211, 24).

Inhibitors of cytokine production are expected to block induciblecyclooxygenase (COX-2) expression. COX-2 expression has been shown to beincreased by cytokines and it is believed to be the isoform ofcyclooxygenase responsible for inflammation (M. K. O'Banion et al.,Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 4888.) Accordingly, inhibitorsof cytokines such as IL-1 would be expected to exhibit efficacy againstthose disorders currently treated with COX inhibitors such as thefamiliar NSAIDs. These disorders include acute and chronic pain as wellas symptoms of inflammation and cardiovascular disease.

Elevation of several cytokines has been demonstrated during activeinflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1and IL-1ra is present in patients with IBD. Insufficient production ofendogenous IL-1ra may contribute to the pathogenesis of IBD (Cominelli,et al., 1996, Aliment Pharmacol Ther. 10, 49). Alzheimer disease ischaracterized by the presence of beta-amyloid protein deposits,neurofibrillary tangles and cholinergic dysfunction throughout thehippocampal region.

The structural and metabolic damage found in Alzheimer disease ispossibly due to a sustained elevation of IL-1 (Holden, et al., 1995, MedHypotheses, 45, 559). A role for IL-1 in the pathogenesis of humanimmunodeficiency virus (HIV) has been identified. IL-1ra showed a clearrelationship to acute inflammatory events as well as to the differentdisease stages in the pathophysiology of HIV infection (Kreuzer, et al.,1997, Clin Exp Immunol. 109, 54). IL-1 and TNF are both involved inperiodontal disease. The destructive process associated with periodontaldisease may be due to a disregulation of both IL-1 and TNF (Howells,1995, Oral Dis. 1, 266).

Proinflammatory cytokines such as TNFα and IL-1β are also importantmediators of septic shock and associated cardiopulmonary dysfunction,acute respiratory distress syndrome (ARDS) and multiple organ failure.In a study of patients presenting at a hospital with sepsis, acorrelation was found between TNFα and IL-6 levels and septiccomplications (Terregino et al., 2000, Ann. Emerg. Med. , 35, 26). TNFαhas also been implicated in cachexia and muscle degradation, associatedwith HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289).Obesity is associated with an increase incidence of infection, diabetesand cardiovascular disease. Abnormalities in TNFα expression have beennoted for each of the above conditions (Loffreda, et al., 1998, FASEB J.12, 57). It has been proposed that elevated levels of TNFα are involvedin other eating related disorders such as anorexia and bulimia nervosa.Pathophysiological parallels are drawn between anorexia nervosa andcancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). Aninhibitor of TNFα production, HU-211, was shown to improve the outcomeof closed brain injury in an experimental model (Shohami, et al., 1997,J Neuroimmunol. 72, 169). Atherosclerosis is known to have aninflammatory component and cytokines such as IL-1 and TNF have beensuggested to promote the disease. In an animal model an IL-1 receptorantagonist was shown to inhibit fatty streak formation (Elhage et al.,1998, Circulation, 97, 242).

TNFα levels are elevated in airways of patients with chronic obstructivepulmonary disease and it may contribute to the pathogenesis of thisdisease (M. A. Higham et al., 2000, Eur. Respiratory J., 15, 281).Circulating TNFα may also contribute to weight loss associated with thisdisease (N. Takabatake et al., 2000, Amer. J. Resp. & Crit. Care Med.,161 (4 Pt 1), 1179). Elevated TNFα levels have also been found to beassociated with congestive heart failure and the level has beencorrelated with severity of the disease (A. M. Feldman et al., 2000, J.Amer. College of Cardiology, 35, 537). In addition, TNFα has beenimplicated in reperfusion injury in lung (Borjesson et al., 2000, Amer.J. Physiol., 278, L3-12), kidney (Lemay et al., 2000, Transplantation,69, 959), and the nervous system (Mitsui et al., 1999, Brain Res., 844,192).

TNFα is also a potent osteoclastogenic agent and is involved in boneresorption and diseases involving bone resorption (Abu-Amer et al.,2000, J. Biol. Chem., 275, 27307). It has also been found highlyexpressed in chondrocytes of patients with traumatic arthritis(Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNFα hasalso been shown to play a key role in the development ofglomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78,1625).

The abnormal expression of inducible nitric oxide synthetase (iNOS) hasbeen associated with hypertension in the spontaneously hypertensive rat(Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in theexpression of iNOS and therefore may also have a role in thepathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension,9, 867).

IL-1 has also been shown to induce uveitis in rats which could beinhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol.and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have beenshown to stimulate proliferation of acute myelogenous leukemia blasts(Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essentialfor the development of both irritant and allergic contact dermatitis.Epicutaneous sensitization can be prevented by the administration of ananti-IL-1 monoclonal antibody before epicutaneous application of anallergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Dataobtained from IL-1 knock out mice indicates the critical involvement infever for this cytokine (Kluger et al., 1998, Clin Exp PharmacolPhysiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 andIL-8 initiate the acute-phase reaction which is stereotyped in fever,malaise, myalgia, headaches, cellular hypermetabolism and multipleendocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).The production of these inflammatory cytokines rapidly follows trauma orpathogenic organism invasion.

Other proinflammatory cytokines have been correlated with a variety ofdisease states. IL-8 correlates with influx of neutrophils into sites ofinflammation or injury. Blocking antibodies against IL-8 havedemonstrated a role for IL-8 in the neutrophil associated tissue injuryin acute inflammation (Harada et al., 1996, Molecular Medicine Today 2,482). Therefore, an inhibitor of IL-8 production may be useful in thetreatment of diseases mediated predominantly by neutrophils such asstroke and myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, hemodialysis, leukopherisis,granulocyte transfusion associated syndromes, and necrotizingenterocolitis.

Rhinovirus triggers the production of various proinflammatory cytokines,predominantly IL-8, which results in symptomatic illnesses such as acuterhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).

Other diseases that are effected by IL-8 include myocardial ischemia andreperfusion, inflammatory bowel disease and many others.

The proinflammatory cytokine IL-6 has been implicated with the acutephase response. IL-6 is a growth factor in a number in oncologicaldiseases including multiple myeloma and related plasma cell dyscrasias(Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has alsobeen shown to be an important mediator of inflammation within thecentral nervous system. Elevated levels of IL-6 are found in severalneurological disorders including AIDS dementia complex, Alzheimer'sdisease, multiple sclerosis, systemic lupus erythematosus, CNS traumaand viral and bacterial meningitis (Gruol, et al., 1997, MolecularNeurobiology 15: 307). IL-6 also plays a significant role inosteoporosis. In murine models it has been shown to effect boneresorption and to induce osteoclast activity (Ershler et al., 1997,Development and Comparative Immunol. 21: 487). Marked cytokinedifferences, such as IL-6 levels, exist in vivo between osteoclasts ofnormal bone and bone from patients with Paget's disease (Mills, et al.,1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shownto be involved in cancer cachexia. The severity of key parameters ofcachexia can be reduced by treatment with anti IL-6 antibodies or withIL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther.1, 107). Several infectious diseases, such as influenza, indicate IL-6and IFN alpha as key factors in both symptom formation and in hostdefense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpressionof IL-6 has been implicated in the pathology of a number of diseasesincluding multiple myeloma, rheumatoid arthritis, Castleman's disease,psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997,Protein Sci. 6, 929). Compounds that interfered with the production ofcytokines including IL-6, and TNF were effective in blocking a passivecutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41,1050).

GM-CSF is another proinflammatory cytokine with relevance to a number oftherapeutic diseases. It influences not only proliferation anddifferentiation of stem cells but also regulates several other cellsinvolved in acute and chronic inflammation. Treatment with GM-CSF hasbeen attempted in a number of disease states including burn-woundhealing, skin-graft resolution as well as cytostatic and radiotherapyinduced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF alsoappears to play a role in the replication of human immunodeficiencyvirus (HIV) in cells of macrophage lineage with relevance to AIDStherapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41).Bronchial asthma is characterised by an inflammatory process in lungs.Involved cytokines include GM-CSF amongst others (Lee, 1998, JR CollPhysicians Lond 32, 56).

Interferon γ (IFN γ) has been implicated in a number of diseases. It hasbeen associated with increased collagen deposition that is a centralhistopathological feature of graft-versus-host disease (Parkman, 1998,Curr Opin Hematol. 5, 22). Following kidney transplantation, a patientwas diagnosed with acute myelogenous leukemia. Retrospective analysis ofperipheral blood cytokines revealed elevated levels of GM-CSF and IFN γ.These elevated levels coincided with a rise in peripheral blood whitecell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). Thedevelopment of insulin-dependent diabetes (Type 1) can be correlatedwith the accumulation in pancreatic islet cells of T-cells producing IFNγ (Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN γ along with TNF,IL-2 and IL-6 lead to the activation of most peripheral T-cells prior tothe development of lesions in the central nervous system for diseasessuch as multiple sclerosis (MS) and AIDS dementia complex (Martino etal., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result inarterial disease that can lead to cardiac and cerebral infarction. Manyactivated immune cells are present in these lesions, mainly T-cells andmacrophages. These cells produce large amounts of proinflammatorycytokines such as TNF, IL-1 and IFN γ. These cytokines are thought to beinvolved in promoting apoptosis or programmed cell death of thesurrounding vascular smooth muscle cells resulting in theatherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76).Allergic subjects produce mRNA specific for IFN γ following challengewith Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342).The expression of a number of cytokines, including IFN γ has been shownto increase following a delayed type hypersensitivity reaction thusindicating a role for IFN γ in atopic dermatitis (Szepietowski, et al,1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologicstudies were performed in cases of fatal cerebral malaria. Evidence forelevated IFN γ amongst other cytokines was observed indicating a role inthis disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501).The importance of free radical species in the pathogenesis of variousinfectious diseases has been established. The nitric oxide synthesispathway is activated in response to infection with certain viruses viathe induction of proinflammatory cytokines such as IFN γ (Akaike, etal., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronicallyinfected with hepatitis B virus (HBV) can develop cirrhosis andhepatocellular carcinoma. Viral gene expression and replication in HBVtransgenic mice can be suppressed by a post-transcriptional mechanismmediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer SeminImmunopathol. 17, 26 1). IFN γ can selectively inhibit cytokine inducedbone resorption. It appears to do this via the intermediacy of nitricoxide (NO) which is an important regulatory molecule in bone remodeling.NO may be involved as a mediator of bone disease for such diseases as:rheumatoid arthritis, tumor associated osteolysis and postmenopausalosteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studieswith gene deficient mice have demonstrated that the IL-12 dependentproduction of IFN γ is critical in the control of early parasiticgrowth. Although this process is independent of nitric oxide the controlof chronic infection does appear to be NO dependent (Alexander et al.,1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an importantvasodilator and convincing evidence exists for its role incardiovascular shock (Kilbourn, et al., 1997, Dis Mon. 43, 277). IFN γis required for progression of chronic intestinal inflammation in suchdiseases as Crohn's disease and inflammatory bowel disease (IBD)presumably through the intermediacy of CD4+ lymphocytes probably of theTH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). Anelevated level of serum IgE is associated with various atopic diseasessuch as bronchial asthma and atopic dermatitis. The level of IFN γ wasnegatively correlated with serum IgE suggesting a role for IFN γ inatopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).

WO 01/01986 discloses particular compounds alleged to having the abilityto inhibit TNF-alpha. Certain compounds disclosed in WO 01/01986 areindicated to be effective in treating the following diseases: dementiaassociated with HIV infection, glaucoma, optic-neuropathy, opticneuritis, retinal ischemia, laser induced optic damage, surgery ortrauma-induced proliferative vitreoretinopathy, cerebral ischemia,hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbonmonoxide or manganese or cyanide poisoning, Huntington's disease,Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosisand other demyelinating diseases, amyotrophic lateral sclerosis, headand spinal cord trauma, seizures, convulsions, olivopontocerebellaratrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-relatedneuropathy, MERRF and MELAS syndromes, Leber's disease, Wernicke'sencephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia,hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyricaminoaciduria, sulfite oxidase deficiency, combined systems disease,lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drugaddiction, drug tolerance, drug dependency, depression, anxiety andschizophrenia. WO 02/32862 discloses that inhibitors of pro-inflammatorycytokines including TNFα are allegedly useful for treating acute andchronic inflammation in the lung caused by inhalation of smoke such ascigarette smoke. TNFα anatagonists are apparently also useful for thetreatment of endometriosis, see EP 1022027 A1 . Infliximab, in clinicaltrials for RA, has also been indicated to be useful for treating variousinflammatory diseases including Behcet's disease, uveitis and ankylosingspondylitis. Pancreatitis may also be regulated by inflammatory mediatorproduction, see J Surg Res 2000 May 15 90(2)95-101; Shock 1998 Sep.10(3):160-75. p38MAP kinase pathway plays an role inB.burgdorferi-elicited infammation and may be useful in treatinginflammation induced by the Lyme disease agent. Anguita, J. et. al., TheJournal of Immunology, 2002,168:6352-6357.

Compounds which modulate release of one or more of the aforementionedinflammatory cytokines can be useful in treating diseases associatedwith release of these cytokines. For example, WO 98/52558 disclosesheteroaryl urea compounds which are indicated to be useful in treatingcytokine mediated diseases. WO 99/23091 discloses another class of ureacompounds which are useful as anti-inflammatory agents. WO 99/32463relates to aryl ureas and their use in treating cytokine diseases andproteolytic enzyme mediated disease. WO 00/41698 discloses aryl ureassaid to be useful in treating p38 MAP kinase diseases.

Compounds active against p38 MAP kinase can also be useful for treatingvarious types of cancers as described in WO 03/068223.

U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclicsubstituted urea compounds which are described as being useful fortreating hypercholesterolemia and atheroclerosis. Di-substituted aryland heteroaryl compounds are also disclosed in U.S. Pat. Nos. 6,080,763;6,319,921; 6,297,381 and 6,358,945. The compounds in the patents arealleged to possess anti-cytokine activity and are therefore useful intreating diseases associated with inflammation.

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of cytokine mediateddiseases. Therefore a need exists for small molecule inhibitors fortreating these diseases with optimized efficacy, pharmacokinetic andsafety profiles.

BRIEF SUMMARY OF THE INVENTION

The work cited above supports the principle that inhibition of cytokineproduction with small molecule compounds will be beneficial in thetreatment of various disease states.

It is therefore an object of the invention to provide compounds offormula (I)

It is a further object of the invention to provide methods for treatingcytokine mediated diseases and pathological conditions involvinginflammation such as chronic inflammatory disease, using the novelcompounds of the invention.

It is yet a further object of the invention to provide pharmaceuticalcompositions and processes of preparation of the above-mentioned novelcompounds.

DETAILED DESCRIPTION OF THE INVENTION

In the broadest generic embodiment, there is provided compounds of theformula (I)

wherein:

-   Ar¹is chosen from (i), (ii) and (iii) below:-   i) a carbocycle substituted by R¹, R² and R^(X),    wherein one E or F is nitrogen and other is carbon, R¹ is covalently    attached to either E or F, and when nitrogen is N—R¹ the double    between E and F is not present;    wherein c is a benzo ring fused to ring d which is a 5-7 membered    heterocyclic ring optionally substituted by an oxo (═O) group and    one to two R groups each independently being H or C1-3 alkyl;-   R¹ is chosen from hydrogen, NO₂, —N(R^(c))₂, J-C(O)— N(R^(c))—,    J-S(O)_(m)—N(R^(c))—, C 1-6 alkylS(O)_(m)—-   or R¹ is chosen from C1-6 alkyl, C3-7 cylcoalkyl, C1-5 alkoxyl or    C3-7 cycloalkoxyl, C1-5 alkylthiol or C3-7 cycloalkylthiol, C1-5    acyl, C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, C2-5    alkenyl, C2-5 alkynyl, heterocycle, heterocycleC1-6 alkyl,    heteroaryl, heteroarylC1-6 alkyl and nitrile; each of the    aforementioned where possible are optionally partially or fully    halogenated or are optionally further substituted with    alkylsulfonylamino, aminocarboxyl, alkoxyl, amino, alkylamino,    dialkylamino, hydroxyl, oxo, nitro or nitrile;-   R² is chosen from:    -   hydrogen, halogen, nitrile, C1-5 alkylS(O)_(m)—, arylS(O)_(m),        J-O— C(O)—O—, N(R^(c))₂—C(O)—(CH₂)_(n)—, C1-6 acetyl, aroyl,        C1-6alkoxycarbonyl, C1-6 alkyl, C3-7cycloalkyl, C1-6 alkoxy,        C3-5cycloalkoxy, C1-5 alkylC1-5 alkoxy, hydroxy, hydroxy C1-5        alkyl, and amino optionally mono- or di-substituted by C1-5        alkyl, aryl or aryl C1-5 alkyl; each of the aforementioned where        possible are optionally partially or fully halogenated or are        optionally further substituted with C1-3 alkyl,        alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,        hydroxyl, oxo, nitro or nitrile;        each R^(x) is chosen from C1-6 alkyl or C3-7 cycloalkyl each        being optionally substituted by C1-3 alkyl and optionally        partially or fully halogenated, C1-4 acyl, aroyl, C1-4 alkoxy,        C1-5alkylS(O)_(m) 13 , each may optionally be partially or fully        halogenated, halogen, C1-6 alkoxycarbonyl, carbocyclesulfonyl;        each R^(c) is independently hydrogen or C1-5 alkyl;-   D, A and B in    of the formula (I) are each independently chosen from N or CH    wherein the hydrogen atom is optionally replaced by R⁶;-   Het is a heterocyclic or heteroaryl ring wherein Het is optionally    substituted by one to three R⁵;-   m is 0,1 or 2-   J is chosen from C 1-10 alkyl and C3-7cycloalkyl each optionally    substituted by R^(b);-   R³, R⁴, R⁶, R⁷ and R⁸ are each independently chosen from hydrogen,    halogen, C1-5alkyl, C1-5 alkoxy, C1-5 alkylC1-5 alkoxy, hydroxy,    hydroxy C1-5 alkyl or amino optionally mono- or di-substituted by    C1-5 alkyl, aryl or aryl C1-5 alkyl;-   R⁵ is:-   R^(a), —O—R^(a), —S(O)_(m)—R^(a), —N(R^(a))₂, —C(O)—R^(a), —NH(CR    ⁷R⁸)_(n)—R^(a), N(R^(a))₂—(CH₂)₁₋₂— —(CR⁷R⁸)_(n)—R^(a),    —O(CR⁷R⁸)_(n)—R^(a), —C(O)—O(CR⁷R⁸)_(n)R^(a), —C(O)(CR⁷R⁸)_(n)—R^(a)    —C(O)C(O)R^(a), —C(O)C(O)OR^(a), —C(O)NHR^(a), or    —C(O)NH(CR⁷R⁸)_(n)—, each optionally substituted by C1-3 alkyl,    halogen or hydroxy,    wherein n is 1-5;-   or R ⁵is aryl, heteroaryl or heterocyclyl each optionally    substituted by R^(a);-   R^(a) and R^(b) are each independently chosen from hydrogen, C1-6    alkyl, hydroxyC1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, carbocycle,    carbocycleC0-2 alkyl, aryl, heterocycle, heteroaryl, C1-5 alkoxy,    C1-5 alkylthio, amino, C1-5 alkylamino, C1-5 dialkylamino,    arylamino, aryl C1-5 alkylamino, diarylamino, C1-5 acyl, C1-5    alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, each of the    aforementioned are optionally partially or fully halogenated, or    R^(a) and R^(b) are chosen from C1-5 alkylsulphonylamino, hydroxy,    oxo, halogen, —CF₃, —CH₂—CF₃, nitro and nitrile, wherein each    carbocycle, heterocycle or heteroaryl for R^(a) and R^(b) is    optionally substituted by amino, C1-3 alkyl, halogen or hydroxy; and-   X is O or S    or the pharmaceutically acceptable salts, acids, esters or isomers    thereof.

In another embodiment, there are provided compounds of the formula (I)as described above and wherein

of the formula (I) is chosen from:

-   Het is-   J is chosen from C1-10 alkyl, aryl and C3-7 cycloalkyl each    optionally substituted by R^(b);-   R² is independently chosen from hydrogen, J-O—C(O)—O—, C 1-6 alkoxy    , C1-6 alkyl, C1-6 acetyl, aroyl, halogen, methoxycarbonyl,    phenylsulfonyl, C1-5 alkylS(O)_(m)— and C3-7 cycloalkyl optionally    substituted by C1-3 alkyl, each R² where possible may be optionally    partially or fully halogenated; R¹ is chosen from H, C1-6 alkyl,    C1-5 alkylS(O)_(m—, J-S(O)) _(m—N(R) ^(c))—, C1-5 alkoxyl, C1-5    alkylthiol , NH₂—C(O)—(CH₂)_(n)—, (R^(c))₂N C1-6 alkyl, C1-5acylNH—,    —NH₂, —NO₂, heteroaryl chosen from pyrazole, triazole, imidazole and    tetrazole, and nitrile;    ring d is a 5-6 membered heterocyclic ring such that rings c and d    fuse to form the following:    where each R is independently H or C 1-3 alkyl;-   R³ and R⁴ are each independently chosen from hydrogen, C1-3 alkoxy,    C1-3 alkyl and halogen;-   n is 1-4;-   R^(a) and R^(b) are each independently chosen from hydrogen, C1-6    alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkylC0-2 alkyl, aryl,    C1-5 alkoxy, C1-5 alkylthio, amino, C1-5 alkylamino, C1-5    dialkylamino, arylamino, C1-5 acyl, C1-5 alkoxycarbonyl, C1-5    acyloxy, C1-5 acylamino, aryl C1-5alkylamino, C1-5    alkylsulphonylamino, hydroxy, halogen, —CF₃, —CH₂—CF₃ nitro,    nitrile,-   or R^(a) and R^(b) are chosen from; heterocycle chosen from    pyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl,    thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxalanyl,    piperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl,    tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone,    1,3-dioxanone, 1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl,    aziridinyl, pentamethylene sulfide, pentamethylene sulfoxide,    pentamethylene sulfone, tetramethylene sulfide, tetramethylene    sulfoxide and tetramethylene sulfone and heteroaryl chosen from    thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl,    tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl,    benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl,    quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl,    pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl,    pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl and    imidazo[4,5-b]pyridinyl; wherein each aryl, heterocycle or    heteroaryl for R^(a) and R^(b) is optionally substituted by amino,    C1-3 alkyl, halogen or hydroxy;-   and X is O.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   Ar¹ is chosen from (i) and (ii);-   R⁵ is:-   a) R^(a), —O—R^(a), —S(O)_(m)—R^(a), —N(R^(a) )₂,    N(R^(a))₂—(CH₂)1-2—, —NH(CR⁷R⁸)_(n)—R^(a), —(CR⁷R⁸)_(n)—R^(a) or    —O(CR⁷R8)_(n)—R^(a);-   or R⁵ is:-   b) —C(O)—R^(a), —C(O)—O(CR⁷R⁸)_(n)—R^(a), —C(O)(CR⁷R⁸)_(n)—R^(a),    —C(O)NHR^(a), —C(O)NH(CR⁷R⁸)_(n)—,—C(O)C(O)R^(a) or —C(O)C(O)OR^(a);    each of the above R ⁵is optionally substituted by C1-3 alkyl,    halogen or hydroxyl, and wherein n is 1-3

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   Ar¹ is:    or Ar1 is cyclobutyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl    and indenyl each substituted with one R¹, one R^(x), and one R²    group;-   R¹ is nitrile, NO₂, NH₂, C1-3acylNH—,-   J-S(O)_(m—N(R) ^(c))— where J is C1-10 alkyl, or R¹ is-   R² is independently chosen from C1-6 alkyl, C1-6 alkylS(O)_(m)—,    C1-3 alkoxy and C3-6 cycloalkyl optionally substituted by C1-3    alkyl, each may optionally be partially or fully halogenated;-   R³ and R⁴ are each independently chosen from hydrogen, C1-3 alkyl,    fluoro and chloro;-   R ⁶is chosen from hydrogen and amino;-   n is 1-2;-   R^(a) and R^(b) are each independently chosen from hydrogen, C1-6    alkyl, C3-7 cycloalkylC0-2 alkyl, aryl, C1-5 alkoxy, amino, C1-5    alkylamino, C1-5 dialkylamino, arylamino, aryl C1-5alkylamino, C1-3    acyl, C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, C1-5    sulphonylamino, hydroxy, halogen, —CF₃, —CH₂—CF₃ nitro, nitrile; or    R^(a) is chosen from pyrrolidinyl, pyrrolinyl, morpholinyl,    thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone,    piperidinyl, piperazinyl, homopiperazinyl, piperidinonyl,    tetrahydropyrimidonyl, aziridinyl, isoxazolyl, oxazolyl, thiazolyl,    thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl,    pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein each    aryl, heterocycle or heteroaryl for R^(a) and R^(b) is optionally    substituted by amino, C1-3 alkyl, halogen or hydroxy.

In yet still another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

-   Ar¹ is-   R¹ is:-   J-S(O)₂—NH—, where J is C1-5 alkyl, or R¹ is nitrile, NO₂, NH₂ or    C1-3acylNH—,-   wherein R^(x)=R² each are independently chosen from C1-5 alkyl, C1-5    alkylS(O)_(m)—, C1-4 alkoxy and and C3-5 cycloalkyl optionally    substituted by C1-2 alkyl, each may optionally be partially or fully    halogenated;-   R⁸ is hydrogen, methyl, ethyl, CH₂OH and CH₂OCH₃.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   R^(a) is chosen from hydrogen, C1-6 alkyl, C3-6 cycloalkylC0-2    alkyl, phenyl, C1-5 alkoxy, amino, C1-5 alkylamino, C1-5    dialkylamino, arylamino, aryl C1-5alkylamino, C1-3 acyl, C1-5    alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, hydroxy, halogen,    —CF₃, —CH₂—CF₃;-   or R^(a) is chosen from morpholinyl, thiomorpholinyl,    thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperazinyl,    homopiperazinyl, pyrrolidinyl, piperidinyl, piperidinonyl,    pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each    phenyl, heterocycle or heteroaryl for R^(a) is optionally    substituted by amino, C1-3 alkyl, halogen or hydroxy.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   R^(a) is chosen from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, phenyl,    C1-5 alkoxy, C1-5 alkoxycarbonyl, amino, C1-5 alkylamino, C1-5    dialkylamino, arylamino, aryl C1-5alkylamino, C1-5 acyloxy, C1-5    acylamino, hydroxy, halogen, —CF₃, —CH₂—CF₃; or R^(a) is chosen    morpholinyl, piperidinyl piperazinyl, homopiperazinyl, pyrrolidinyl    and pyridinyl wherein each phenyl, heterocycle or heteroaryl for    R^(a) is optionally substituted by amino, C1-3 alkyl, halogen or    hydroxy.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

of the formula (I) is chosen from:

-   Het is;-   Ar1 is-   R⁵ is:-   C1-5 alkyl, C3-6 cycloalkyl, N(R^(a))₂(CH₂)₁-2—, halogen, C1-3    alkoxy, hydroxy, —N(R^(a))₂, —CF₃, —CH₂—CF₃, aryl,    —S(O)_(m)—R^(a),—NH(CR⁷R⁸)_(n)—R^(a) or —(CR⁷R⁸)_(n)—N(R^(a))₂ each    optionally substituted by C1-3 alkyl, halogen or hydroxy,-   or R⁵ is —C(O)R^(a), —C(O)C(O)R^(a), —C(O)NHR^(a).-   R^(a) is chosen from hydrogen, morpholinyl, piperidinyl,    piperazinyl, pyrrolidinyl, pyridinyl, C₁₋₅ mono or dialkylamino,    arylamino, C3-6cylcoalkyl, C1-5 alkyl and C1-3 alkoxy wherein each    phenyl or heterocycle for R^(a) is optionally substituted by amino,    C1-3 alkyl, halogen or hydroxyl.

The following are preferred embodiments of Het combined with

and wherein Ar¹, X, R³, R⁴ of the formula (I) are as defined in any oneof the first seven embodiments provided hereinabove and wherein:

The following are representative compounds of the invention which can bemade according to the general schemes and working examples below: TABLEI Structure Name

[2-(4-{1-[5-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]- 1H-1,2,3-triazol-4-yl}-2-phenyl-2H-pyrazol-3-yl)-ethyl]-carbamic acid benzyl ester

3-[4-(1-Benzyl-2-ethyl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-4-methyl-benzamide

3-[4-(1-Cyclopropyl-5-ethyl-1H- pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(1-Isopropyl-5-methyl-1H- pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(1-tert-Butyl-5-methyl-1H- pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(2-Acetyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert- butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-[4-(2-Benzenesulfonyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-4-methyl-benzamide

3-[4-(2-Benzoyl-3-methyl-3H- imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-4-methyl-benzamide

3-[4-(2-Benzoyl-3-methyl-3H- imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(2-Benzyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert- butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-[4-(2-Benzyloxymethyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]- N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-4-methyl-benzamide

3-[4-(2-Cyclobutyl-3-methyl-3H- imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(2-Cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(2-Cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[5-(2-hydroxy-1,1-dimethyl-ethyl)-3- methanesulfonylamino-2-methoxy-phenyl]-4-methyl-benzamide

3-[4-(2-Isopropyl-3-methyl-3H- imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(2-tert-Butyl-3-methyl-3H- imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(3-Benzyl-2-ethyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-4-methyl-benzamide

3-[4-(3-tert-Butyl-2-cyclopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-4-methyl-benzamide

3-[4-(3-tert-Butyl-2-methyl-3H- imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(3-tert-Butyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-[4-(3-tert-Butyl-3H-imidazol-4-yl)- 1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4- yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4- yl)-imidazol-1-yl]-N-(2-methoxy-5-trifluoromethyl-phenyl)-4-methyl- benzamide

3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4- yl)-imidazol-1-yl]-N-(3-methanesulfonylamino-2-methoxy-5- trifluoromethyl-phenyl)-4-methyl-benzamide

3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4- yl)-imidazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4- yl)-imidazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

3-[4-(6-Amino-pyridin-3-yl)-1,2,3- triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-4-methyl-benzamide

3-{4-[1-(1-Benzyl-piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol- 1-yl}-N-(5-ert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-4-methyl-benzamide

3-{4-[2-(1-Benzyloxy-cyclopropyl)-3- methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-{4-[2-(2-Benzyloxy-1,1-dimethyl- ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-{4-[2-(4-Benzyl-piperazin-1-yl)-1- methyl-1H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-{4-[2-(4-Benzyl-piperazin-1-yl)-3- methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-{4-[2-(Hydroxy-phenyl-methyl)-3- methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-[3- methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4- methyl-benzamide

3-{4-[5-(2-Amino-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-4-methyl-benzamide

4-(4-{1-[5-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]- 1H-1,2,3-triazol-4-yl}-2-cyclopropyl-2H-pyrazol-3-yl)-piperidine-1- carboxylic acid tert-butyl ester

N-(5-tert-Butyl-2-methanesulfinyl- phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-2-methanesulfinyl- phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-2-methanesulfinyl- phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1- yl}-4-methyl-benzamide

N-(5-tert-Butyl-2-methoxy-phenyl)-3- [4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)- imidazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-{4-[6-(cyclopropylmethyl-amino)- pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3-{[(2-dimethylamino- ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-4-methyl-3-(4- pyridin-3-yl-1,2,3-triazol-1-yl)-benzamide

N-(5-tert-Butyl-3-cyano-2-methoxy- phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3-cyano-2-methoxy- phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3-cyano-2-methoxy- phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1- yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-(4-furan-3-yl-1,2,3-triazol- 1-yl)-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-(4-pyridin-3-yl-1,2,3-triazol- 1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3,4-dimethyl-5-(4-pyridin-3- yl-1,2,3-triazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-tert-butyl-5-methy[-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5- isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1- yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5- piperidin-4-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-dimethyl-1H- pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,2-diethyl-1H-imidazol-4-yl)-1,2,3-triazol-l-yl]-4-methyl- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-diisopropyl-1H- pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-ethyl-3H-imidazol-4- yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-isopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3- isopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-dimethylamino-1- methyl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfonyl-3- methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfinyl-3- methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butylsulfanyl-3- methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-hydroxymethyl-3- methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-formyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclobutyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-dimethylamino-3- methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2,3-diethyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2,3-dihydro-imidazo[2,1- b]thiazol-5-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-cyclopropyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-cyclopropyl-2- isopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-tert-butyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-ethyl-2-phenyl-3H- imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H- pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-cyclopropyl-1- isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-isopropyl-1-phenyl- 1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-cyclopropyl-1-phenyl- 1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5,5-dimethyl-6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,3]triazol-1- yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-dimethylamino- pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-cyclopropylamino- pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-[4-(7,7-dimethyl-6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-1,2,3-triazol-1-yl]-4-methyl- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol- 1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(4-fluoro-phenyl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol- 1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(1-tert-butyl-piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl]-1,2,3- triazol-1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-cyclopropyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(hydroxy-phenyl- methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(2,2-dimethyl- propionyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-2,2- dimethyl-propyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4- methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-1-methyl- ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(2-hydroxy-1,1- dimethyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy- cyclopropyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-ethyl)-3- methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(cyclopropyl-hydroxy-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[5-(2-dimethylamino- ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino- ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl- amino)-pyridin-3-yl]-12,3-triazol-1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino-ethylamino)-pyridin-3-yl]-1,2,3-triazol- 1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-5-methoxy-pyridin-3-yl]-1,2,3- triazol-1-yl}-4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-3-fluoro-4-methyl-5-(4- pyridin-3-yl-1,2,3-triazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-chloro-3-(4-pyridin-3-yl- 1,2,3-triazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-fluoro-3-(4-pyridin-3-yl- 1,2,3-triazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H- imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl- 1,2,3-triazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-methyl- pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1- yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-methyl- pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl- imidazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6- methylamino-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-thiazol-5-yl- 1,2,3-triazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyrimidin-5-yl- 1,2,3-triazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6- trifluoromethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(tetrahydro- furan-3-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol- 1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(4-methyl- pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2- phenylsulfanyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1- phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-methyl-1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4- yl]-1,2,3-triazol-1-yl}-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[2-methyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazol-4- yl]-1,2,3-triazol-1-yl}-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1- pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-morpholin-4-yl-thiazol-5-yl)-1,2,3-triazol-1-yl]- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[6-(2- methylamino-ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[6-(2- morpholin-4-yl-ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H- imidazol-4-yl)-pyrazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2- pyridin-4-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-piperidin-4-yl-1H-pyrazol-4-yl)-1,2,3- triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-4-yl- [1,2,3]triazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-2-yl- [1,2,3]triazol-1-yl)-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5,6,7,8- tetrahydro-imidazo[1,2-a]pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl -2-phenyl-3H-imidazol-4-yl)-1,2,3-triazol- 1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-(2- morpholin-4-yl-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-1,2,3- triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(1-methyl-2- piperazin-1-yl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-beflzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2- piperazin-1-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-cyclohexane)]-[1,2,3]triazol- 1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(1- methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2- morpholin-4-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-(2′-methyl-cycloproane))]- [1,2,3]triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2- methylsulfanyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-{3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazol-4- yl]-1,2,3-triazol-1-yl}-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(2- methyl-propane-2-sulfonyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}- benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methyl-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]- 4-methyl-benzamide

N-(5-tert-Butyl-3- methanesulfonylamino-2-methyl-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl- benzamide

N-[3-Methanesulfonylamino-2- methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(5-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

N-[3-Methanesulfonylamino-2- methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol- 1-yl]-benzamide

N-[3-Methanesulfonylamino-2- methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-{4-[3-methyl-2-(1- methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamide

N-[3-Methanesulfonylamino-2- methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazol-4- yl]-1,2,3-triazol-1-yl}-benzamide

N-[5-(2-Hydroxy-1,1-dimethyl-ethyl)- 3-methanesulfonylamino-2-methoxy-phenyl]-4-methyl-3-{4-[3-methyl-2-(1- methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideor the pharmaceutically acceptable salts, acids, esters or isomersthereof

In all the compounds disclosed hereinabove in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

Of particular importance according to the invention are compounds offormula (I) for use as pharmaceutical compositions with an anti-cytokineactivity.

The invention also relates to the use of a compound of formula (I) forpreparing a pharmaceutical composition for the treatment and/orprevention of a cytokine mediated disease or condition or oncologicaldisease.

The invention also relates to pharmaceutical preparations, containing asactive substance one or more compounds of formula (I) or thepharmaceutically acceptable derivatives thereof, optionally combinedwith conventional excipients and/or carriers.

The invention includes the use of any compounds of described abovecontaining one or more asymmetric carbon atoms may occur as racematesand racemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereomers. All such isomeric forms of these compounds areexpressly included in the present invention. Each stereogenic carbon maybe in the R or S configuration, or a combination of configurations.

‘Isomer’ shall be understood to include any of the compounds asdescribed above as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. All such isomericforms of these compounds are expressly included in the presentinvention.

Some of the compounds of formula (I) can exist in more than onetautomeric form. The invention includes methods using all suchtautomers.

The invention includes the use of any compounds of described abovecontaining one or more isotopically-labelled form. Anisotopically-labelled form of an active agent of a combination of thepresent invention is identical to said active agent but for the factthat one or more atoms of said active agent have been replaced by anatom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, 15N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C1-4alkoxy” is a C1-4alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl and alkynyl groupsshall be understood as being branched or unbranched where structurallypossible and unless otherwise specified. Other more specific definitionsare as follows:

Carbocycles include hydrocarbon rings containing from three to twelvecarbon atoms. These carbocycles may be either aromatic either aromaticor non-aromatic ring systems. The non-aromatic ring systems may be mono-or polyunsaturated. Preferred carbocycles include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certainterms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be usedinterchangeably.

The term “heterocycle” refers to a stable nonaromatic 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 memberedbicyclic heterocycle radical which may be either saturated orunsaturated. Each heterocycle consists of carbon atoms and one or more,preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure. Unless otherwise stated,heterocycles include but are not limited to, for example pyrrolidinyl,pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene sulfoxide,pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxideand tetramethylene sulfone.

The term “heteroaryl” shall be understood to mean an aromatic 5-8membered monocyclic or 8-11 membered bicyclic ring containing 1-4heteroatoms such as N,O and S. Unless otherwise stated, such heteroarylsinclude aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl,thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl,quinazolinyl, naphthyridinyl, indazolyl, triazolyl,pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl,pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl andimidazo[4,5-b]pyridinyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

In all alkyl groups or carbon chains one or more carbon atoms can beoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in defintions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

The term “aryl” as used herein shall be understood to mean aromaticcarbocycle or heteroaryl as defined herein. Each aryl or heteroarylunless otherwise specified includes it's partially or fully hydrogenatedderivative. For example, quinolinyl may include decahydroquinolinyl andtetrahydroquinolinyl, naphthyl may include it's hydrogenated derivativessuch as tetrahydranaphthyl. Other partially or fully hydrogenatedderivatives of the aryl and heteroaryl compounds described herein willbe apparent to one of ordinary skill in the art.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen. .For example, for an —S—C1-6 alkyl radical, unless otherwise specified,this shall be understood to include —S(O)—C1-6 alkyl and —S(O)₂—C1-6alkyl, likewise, —S—R^(a) may be represented as phenyl-S(O)_(m)— whenR^(a) is phenyl and where m is 0, 1 or 2.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine, preferablyfluorine. The definitions “partially or fully halogenated”; partially orfully fluorinated; “substituted by one or more halogen atoms”, includesfor example, mono, di or tri halo derivatives on one or more carbonatoms. For alkyl, a nonlimiting example would be —CH₂CHF₂, —CF₃ etc.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the inventive methodsdisclosed herein.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the formula (I).

Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic and organic acids and bases.Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric andbenzenesulfonic acids. Other acids, such as oxalic acid, while notthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsand their pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N—(C ₁-C₄ alkyl)₄ ⁺ salts.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple chemical transformation, are modified to produce compoundsof the invention. Simple chemical transformations include hydrolysis,oxidation and reduction. Specifically, when a prodrug is administered toa patient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

General Synthetic Methods

The invention additionally provides for methods of making the compoundsof formula (I). The compounds of the invention may be prepared by thegeneral methods and examples presented below, and methods known to thoseof ordinary skill in the art. In the schemes below, unless otherwisespecified, Ar¹, R¹-R⁶ and X in the formulas shown below shall have themeanings defined for these groups in the definition of the formula (I)of the invention, described hereinabove. Intermediates used in thesyntheses below are either commercially available or easily prepared bymethods known to those skilled in the art. Further reference in thisregard may be made to U.S. Pat. No. 6,358,945, U.S. application Ser.Nos. 09/714,539, 09/834,797, 10/120,028, 10/143,322 and 10/147,675, U.S.provisional application Nos. 60/567,693, 60/526,569, 60/570,284. Each ofthe aforementioned are incorporated in their entirety.

Reaction progress may be monitored by conventional methods such as thinlayer chromatography (TLC). Intermediates and products may be purifiedby methods known in the art, including column chromatography, HPLC orrecrystallization.

In the discussion below, Q represents the ring between the phenyl ringand het of formula I as shown below:

Compounds of formula (I) having Q=a triazole (A=B=N, D=CH) may beprepared as illustrated in Scheme I. An azide intermediate II is reactedwith a heteroaryl acetylene intermediate III in a suitable solvent suchas EtOH, optionally in the presence of a copper salt such as CuSO₄ withan appropriate reductant such as sodium ascorbate (Rostovtsev, V. V. etal. Angew. Chem., Int. Ed. Engl. 2002, 41, 2596), and optionally whileheating to provide the triazole intermediate IV. Coupling of thecarboxylic acid of IV with the desired aniline Ar¹NH₂ using standardcoupling conditions known in the art provides the desired compound offormula (I) or a precursor which may be further modified by methodsknown in the art to provide the desired compound of formula (I). Theheteroaryl acetylene intermediate III may be prepared by reaction ofintermediate V, where X is I, Br, Cl or —OSO₂CF₃, withtrimethylsilylacetylene VI, in the presence of a suitable catalyst suchas (Ph₃P)PdCl₂, a copper salt such as CuI and a suitable base such asEt₃N, followed by reaction with tetrabutylammonium bromide to remove thetrimethylsilyl group. Alternatively, one may react a heteroaryl aldehydeVII with dimethyl 2-oxo-1-diazopropylphosphinate in the presence of asuitable base such as K₂CO₃ to provide the desired intermediate III.

The sequence of reactions may be reversed as illustrated in Scheme II.Using this procedure, the amide coupling step is carried out first withintermediate II to provide intermediate VIII. This is then followed byreaction with the heteroaryl acetylene intermediate III to provide thedesired compound of formula (I).

Heteroaryl aldehydes VII shown in Scheme I may be commercially availableor readily prepared from commercially available intermediates by methodsknown in the art. For example, as illustrated in Scheme III, heteroarylaldehydes may be prepared by direct reduction of the corresponding esterIX, for example by reaction with diisobutylaluminum hydride.Alternatively, one may reduce the ester IX to an alcohol X by treatmentwith a suitable reducing agent such as lithium aluminum hydride. Thealcohol can then be oxidized to aldehyde VII by treatment with asuitable oxidizing agent such as MnO₂. Starting esters XI may becommercially available, prepared from commercially available carboxylicacids or prepared by methods known in the art. In addition, manyheteroaryl aldehydes may be prepared by direct formylation of aheteroaryl moiety. For example, treatment of an optionally substitutedheteroaryl moiety XI with a suitable base such as n-BuLi, in a suitablesolvent such as THF, preferably while cooling at about −78° C., followedby treatment with a formylating agent such as dimethylformamide (XII)provides a heteroaryl aldehyde VII.

Compounds of formula (I) having Q=imidazole (B=N; A=D=CH) may beprepared as described in Scheme IV. Aniline intermediate XIII is reactedwith a heteroaryl ketone XIV where Y is a leaving group such as Cl, Bror I, to provide the substituted aniline XV. Reaction of XV with athiocyanate salt such as potassium thiocyanate provides the2-mercaptoimidazole intermediate XVI. Treatment of XVI with NaNO₂ inHNO₃ provides imidazole intermediate XVII. Intermediate XVII may then behydrolyzed and coupled with the desired aniline intermediate asdescribed above to provide the desired compound of formula (I).

Another method that may be used to obtain compounds of formula (I) isillustrated in Scheme V. Halogenated intermediate XVIII, where hal=Br, Ior Cl, may be coupled with a derivatized heteroaryl moiety (M-Het) usingreactions well known in the art. For example, if M is a trialkyltinmoiety one may perform a Stille coupling (see for example J. K. Stille,Angew. Chem. Int. Ed. Engl., 1986, 25, 508; for a review, see V. Farinaet al., Org. Reac., 1997, 50, 1). Alternatively, if M is a boronic acidgroup, one may perform a Suzuki cross coupling reaction (see for exampleJ. Hassan et al., Chem Rev., 2002, 102, 1359 and N. Miyaura and A.Suzuki, Chem. Rev., 1995, 95, 2457) to obtain the desired compound.

A more specific example is illustrated in Scheme V for the synthesis ofa compound of formula (I) having Q=pyrazole (X═Y═N; W═Z═C). Using thismethod the phenyl hydrazine intermediate XIX is treated withmalondialdehyde(bismethylacetal) in the presence of an acid such as HCIto provide pyrazole XX. Halogenation, for example by treatment of XXwith bromine, provides XXI (Hal=Br). Treatment of XXI withtrialkylstannanylheteroaryl intermediate, for example atributylstannanylheteroaryl XXII, in the presence of a palladiumcatalyst such as Pd(PPh₃)₄, in a suitable solvent such as dioxane, whileheating at about 100° C., provides coupled intermediate XXIII.Hydrolysis of the ester on intermediate XXIII, and coupling of theresulting carboxylic acid with an aniline intermediate as describedabove in Schemes I and IV provides the desired compound of formula (I).

SYNTHETIC EXAMPLES

Abbreviations

-   Boc tert-butyloxycarbonyl-   m-CPBA m-Chloro-peroxybenzoic acid-   CDI Carbonyl diimidazole-   DIBAL-H Diisobutyl aluminum hydride-   DIPEA N,N-Diisopropyl ethylamine-   DMAP 4-Dimethylaminopyridine-   DMF Dimethylformamide-   HATU O-(7-azabenzotriazol-1-yl)-N,N, N' N'-tetramethyluronium    hexafluorophosphate-   HOBt 1-Hydroxybenzotriazole-   LHMDS Lithium hexamethyldisilazide-   MTBE Methyl tert-butyl ether-   NMP N-methyl-2-pyrrolidinone-   PS Polystyrene-   TBAF Tetrabutylammonium fluoride-   TBD 1,5,7-Triazabicyclo[4.4.0]dec-5-ene-   THF Tetrahydrofuran-   TMEDA Tetramethylethylenediamine-   TMS Trimethylsilyl

Example 1N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-chloro-pyridin-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

To 2-chloro-5-iodopyridine (Aldrich; 2.44 g, 10.2 mmol), (PPh₃)₂PdCl₂(360 mg, 0.51 mmol) and CuI (97 mg, 0.51 mmol) under N₂ were added 35 mLof Et₃N and 1.00 g (10.2 mmol) of Me₃SiCCH. The pale green/brownsuspension was stirred for six days under N₂. The mixture wasconcentrated and the resulting suspension was stirred with 50 mL of hothexanes, and the orange solution was separated from the the insolublematerial. The remaining residue was washed three more times with hothexanes, and the combined washes were concentrated and chromatographed.After careful concentration, 1.4 g of2-chloro-5-trimethylsilanylethynyl-pyridine was obtained as a beigesolid. A 1 M solution of TBAF in THF (12 mL) was added to 500 mg (2.38mmol) of 2-chloro-5-trimethylsilanylethynyl-pyridine and the blacksolution was stirred overnight. The mixture was concentrated, theresulting residue was stirred in 50 mL of Et₂O for 1 h, and the liquidwas decanted from the solids. This washing procedure was repeated twice,and the combined washes were concentrated and chromatographed to provide240 mg of 2-chloro-5-ethynylpyridine as a colorless solid.

To a suspension of 308 mg (1.75 mmol) of 3-azido-4-methyl benzoic acid(U.S. Ser. No. 04/102492) and 240 mg (1.75 mmol) of2-chloro-5-ethynylpyridine in 1 mL of water and 2 mL of EtOH was added243 μL (1.75 mmol) of Et₃N. To this solution was added 1.75 mL of 1Maqueous sodium ascorbate followed by 1.75 mL of 0.1 M aqueous of CuSO₄and the resulting yellow suspension was stirred for two days. A 1 Msolution of acetic acid in water (1.75 mL) was added along with anadditional 2 mL of water. The suspension was stirred for 1h, then wasfiltered, washed with water (2×2 mL) and hexanes (2×10 mL), and driedunder suction to provide 470 mg of3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid.

3-[4-(6-Chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid(470 mg; 1.49 mmol),N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (WO02/083628) (488 mg; 1.79 mmol), and 0.87 mL (5.0 mmol) of DIPEA werecombined in 15 mL DMF. Then 1.14 g (2.99 mmol) of HATU and 403 mg (2.99mmol) of HOBt were added and the dark brown solution was stirredovernight at room temperature. The mixture was then partitioned betweenEtOAc and water. The layers were separated and the organic portion waswashed with water (2×50 mL), brine (50 mL), dried (MgSO₄), filtered, andconcentrated. Chromatography provided 375 mg (0.66 mmol; 44%) of thetitle compound with 95% purity. ESI MS m/z 569 [C₂₇H₂₉ClN₆O₄S+H]⁺.

Example 2N-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

A solution of 500 mg (2.09 mmol) of 2-chloro-5-iodo pyridine in 1.64 g(23.1 mmol) of aminomethylcyclopropane was heated to 100° C in a sealedtube for 48h. The mixture was then concentrated, dissolved in EtOAc,washes with water and brine, dried with MgSO₄, filtered, andconcentrated. Recrystallization from hexanes provided 440 mg (1.61 mmol;77%) of cyclopropylmethyl-(5-iodo-pyridin-2-yl)-amine. ESI MS m/z 275[C₉H₁₁ IN₂+H]⁺.

To 1.14 g (4.16 mmol) of cyclopropylmethyl-(5-iodo-pyridin-2-yl)-amine,150 mg (0.21 mmol) of (PPh₃)₂PdCl₂, and 40 mg (0.21 mmol) of CuI underN₂ were added 11 mL of Et₃N and 0.59 mL (8.3 mmol) of Me₃SiCCH. The palegreen/yellow suspension was stirred overnight, concentrated, and thenpartitioned between EtOAc and water. The organic portion was washed withwater, brine, dried (Na₂SO₄), filtered, concentrated, andchromatographed (0-30% EtOAc in hexanes) provided a red-brown solid. Theresidue was stirred with 10 mL of refluxing hexanes. The mixture wasfiltered, and the solids were washed twice with 5 mL of hot hexanes. Thefiltrate and washes were combined and concentrated to provide 855 mg ofcyclopropylmethyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine as ayellow fluffy solid.

To a 0° C. solution of 855 mg (3.50 mmol) ofcyclopropylmethyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine in 7 mLof THF, was slowly added 7.0 mL (7.0 mmol) of 1M TBAF in THF. Themixture was stirred for 2 h, then poured into water and extracted withEt₂O. The Et₂O was washed with brine. The washes were extracted oncewith Et₂O, and the combined extracts were diluted with 10 mL of CH₂Cl₂and left to sit for 10 min. The solution was then decanted from thewater that had separated, and was dried with Na₂SO₄, filtered,concentrated, and chromatographed (1-20% EtOAc in hexanes) to provide467 mg of 2-(cyclopropylmethyl)amino-5-ethynyl pyridine.

3-Azido-4-methyl benzoic acid (497 mg; 2.81 mmol) was suspended in 6.5mL of EtOH. To this mixture was added 4N NaOH until the mixture becamehomogeneous, followed then by 2-(cyclopropylmethyl)amino-5-ethynylpyridine (460 mg; 2.61 mmol) and 529 mg (2.67 mmol) of sodium ascorbatein 0.7 mL of water. The mixture was stirred rapidly as 2.67 mL of a 0.1M CuSO₄ solution was added. A yellow precipitate formed and the mixturewas stirred rapidly for 14 h. The mixture was poured into water andacidified carefullly with HOAc. The resulting precipitate was filteredand washed with water. A fine yellow powder was isolated. This materialwas crushed in 1 mL of MeOH and 5 mL of NH₄OH was added. The resultinggreen mixture was stirred for 10 min, then HOAc was carefully addeduntil a white precipitate formed (pH 8-9). The precipitate was filteredand washed with 1% HOAc in water, then with water and hexanes to provide607 mg (1.74 mmol; 65%) of3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzoicacid.

Example 2 was prepared by coupling3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzoicacid with 5-tert-butyl-2-methyl-pyridin-3-ylamine (See U.S. provisionalapplication 60/567,693) in the same manner as Example 1. ESI MS m/z 496[C₂₉H₃₃N₇O+H]⁺.

Example 3N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-benzamide

4-Methyl-3-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-benzoic acid wasprepared from 3-azido-4-methyl benzoic acid and 2-ethynyl pyridine(Aldrich) in the same manner as3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid(Example 1).

Example 3 was prepared by coupling4-methyl-3-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-benzoic acid withN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in thesame manner as Example 1. ESI MS m/z 533 [C₂₇H₃₀N₆O₄S+H]⁺.

Example 4N-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

Example 4 was prepared by coupling3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methoxy-benzoicacid with 3-amino-5-tert-butyl-2-methyl-benzonitrile (See U.S.provisional application 60/567,693) in the same manner as Example 1. ESIMS m/z 536 [C₃₁H₃₃N₇O+H]⁺.

Example 5N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-fluoro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzamide

4-Fluoro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid wasprepared from 3-azido-4-fluoro benzoic acid (U.S. Ser. No. 04/102492)and 3-ethynyl pyridine (Aldrich) in the same manner as3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid(Example 1).

Example 5 was prepared by coupling4-fluoro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid withN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in thesame manner as Example 1. ESI MS m/z 539 [C₂₆H₂₇FN₆O₄S+H]⁺.

Example 6N-(5-tert-Butyl-2-methanesulfinyl-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

Example 6 was prepared by coupling3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzoicacid with 5-tert-butyl-2-methanesulfinyl-phenylamine (see U.S.provisional application 60/526,569) in the same manner as Example 1. ESIMS m/z 543 [C₃₀H₃₄N₆O₂S+H]⁺.

Example 7N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide

In a flask under N₂ were added 87 mg (0.23 mmoL) of (CH₃CN)₂PdCl₂ and 36mg (0.19 mmol) of CuI, followed by 5 mL of dioxane, 131 mg (0.454 mmol)of t-BuP.HBF₄, 649 mg (3.77 mmol) of 2-methyl-5-bromo pyridine (Fluka),1.3 mL (9.4 mmol) of Me₃SiCCH, and finally 0.64 mL (4.5 mmol) ofi-Pr₂NH. The mixture was stirred for one hour, filtered through celite,and the celite was washed with EtOAc. The filtrate was washed with waterand brine, and the washes were extracted once with EtOAc. The combinedextracts were dried with Na₂SO₄, filtered, concentrated, andchromatographed (0-2% MeOH in CH₂Cl₂) to provide 646 mg of2-methyl-5-trimethylsilanylethynyl-pyridine.

A mixture of 654 mg (3.45 mmol) of2-methyl-5-trimethylsilanylethynyl-pyridine and 8 mL of 1 M TBAF in THFwas stirred for 2 h. The mixture was concentrated and chromatographed(10-50% EtOAc in hexanes) to provide 301 mg of 2-methyl-5-ethynylpyridine.

4-Methyl-3-[4-(6-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acidwas prepared from 3-azido-4-methyl benzoic acid and 2-methyl-5-ethynylpyridine in the same manner as3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid(Example 1).

Example 7 was prepared by coupling4-methyl-3-[4-(6-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acidwith N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide inthe same manner as Example 1. ESI MS m/z 547 [C₂₈H₃₂N₆O₄S+H]⁺.

Example 8N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzamide

A suspension of 100 mg (0.52 mmol) of 3-azido-4,5-dimethyl benzoic acid(U.S. Ser. No. 04/102492), 54 mg (0.52 mmol) of 3-ethynyl pyridine, and200 μL of EtOH was heated to 120° C. in a sealed tube for 12 h. Themixture was cooled and diluted with 500 μL of EtOH. The mixture wasfiltered and the solids were washed with EtOH (3×0.5 mL). The solidswere dried to provide 50 mg of3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid.

Example 8 was prepared by coupling3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid withN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in thesame manner as Example 1. ESI MS m/z 549 [C₂₈H₃₂N₆O₄S+H]⁺.

Example 9N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide

To an ice-cold suspension of 3-hydroxy-2-methylpyridine (2.00 g; 18.3mmol) and N-phenyltriflimide (6.55 g; 18.3 mmol) in 50 mL of CH₂Cl₂ wasadded dropwise 2.70 mL (19.4 mmol) of Et₃N. The resulting suspension wasstirred for 1 h at 0° C. and for an additional 2 h at room temperature.The mixture was then washed twice with 20 mL of 1M NaOH, once withhalf-saturated K₂CO₃, and once with brine. The extract was dried withNa₂SO₄, filtered, and concentrated to provide trifluoro-methanesulfonicacid 2-methyl-pyridin-3-yl ester as a pale brown oil. ESI MS m/z 242[C₇H₆F₃NO₃S+H]⁺.

2-Methyl-3-ethynyl pyridine was prepared from trifluoro-methanesulfonicacid 2-methyl-pyridin-3-yl ester in the same manner as2-chloro-5-ethynyl-pyridine (Example 1).

4-Methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid(5:3 mixture with4-methyl-3-[5-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid)was prepared from 3-azido-4-methyl benzoic acid and 2-methyl-3-ethynylpyridine in the same manner as3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid(Example 8).

Example 9 was prepared by coupling4-methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid(5:3 mixture with4-methyl-3-[5-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid)with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide inthe same manner as Example 1. Preparative HPLC was used to separateN-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamidefromN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[5-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide.ESI MS m/z 549 [C₂₈H₃₂N₆O₄S+H]⁺.

Example 10N-(5-tert-Butyl-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzamide

4-Methyl-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid wasprepared from 3-azido-4-methyl benzoic acid and 3-ethynyl pyridine(Aldrich) in the same manner as3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid(Example 1).

Example 10 was prepared by coupling4-methyl-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid withN-(3-amino-5-tert-butyl-2-methoxy-benzyl)-N,N′,N′-trimethyl-ethane-1,2-diamine(see U.S. provisional application 60/526,569) in the same manner asExample 1. ESI MS m/z 554 [C₃₂H₄₁N₇O₂−H]⁻.

Example 11N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-chloro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzamide

4-Chloro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid wasprepared from 3-azido-4-chloro benzoic acid (U.S. Ser. No. 04/102492)and 3-ethynyl pyridine (Aldrich) in the same manner as3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid(Example 1).

Example 11 was prepared by coupling4-chloro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid withN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in thesame manner as Example 1. ESI MS m/z 555 [C₂₆H₂₇ClN₆O₄S+H]⁺.

Example 12N-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(5-methoxy-pyridin-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

5-Ethynyl-3-methoxy pyridine was prepared from 5-bromo-3-methoxypyridine (Frontier) in the same manner as 2-chloro-5-ethynyl-pyridine(Example 1).

3-[4-(5-Methoxy-pyridin-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzoic acidwas prepared from 3-azido-4-methyl benzoic acid and 5-ethynyl-3-methoxypyridine in the same manner as3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid(Example 1).

Example 12 was prepared by coupling3-[4-(5-methoxy-pyridin-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzoic acidwithN-[3-amino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-methanesulfonamide(U.S. Ser. No. 04/102492) in the same manner as Example 1. ESI MS m/z563 [C₂₈H₃₀N₆O₅S+H]⁺.

Example 13N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide

4-(5-Ethynyl-pyridin-2-ylmethyl)-morpholine was prepared from4-(5-bromo-pyridine-2-ylmethyl)-morpholine (U.S. Pat. No. 6,358,945) inthe same manner as 2-methyl-5-ethynyl pyridine (Example 7).

A suspension of 87.5 mg (0.494 mmol) of 3-azido-4-methyl-benzoic acidand 100 mg (0.494 mmol) of 4-(5-ethynyl-pyridin-2-ylmethyl)-morpholinewere suspended in 200 μL of EtOH and heated to 140° C. for 1 h in amicrowave reactor. After cooling, the mixture was concentrated toprovide 150 mg of4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzoicacid, and its triazole isomer4-methyl-3-[5-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzoicacid in a 2:1 ratio

Example 13 was prepared by coupling4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoicacid (2:1 with4-methyl-3-[5-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzoicacid) with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamidein the same manner as Example 1. Chromatography separated the triazoleisomers. ESI MS m/z 635 [C₃₂H₃₉N₇O₅S+H]⁺.

Example 14N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzamide

4-Methyl-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzoic acid (76.3 mg;0.272 mmol) was suspended in 5 mL of CH₂Cl₂, and 1 mL of THF, and 0.04mL (0.4 mmol) of oxalyl chloride was added. One drop of DMF was thenadded to the stirring suspension, and the mixture was stirred for 2 h.The resulting cloudy solution was concentrated to dryness and suspendedin CH₂Cl₂. N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide(81 mg; 0.30 mmol) was added, then 0.06 mL (0.5 mmol) of 2,6-lutidine,and the resulting solution was stirred overnight. The mixture was thenwashed with 1M NaHSO₄, saturated NaHCO₃, and brine. The organic portionwas dried with Na₂SO₄, filtered, and concentrated. Chromatography(0-6.5% MeOH in CH₂Cl₂), with careful selection of only the purefractions, provided 80 mg (0.15 mmol; 55%) of Example 14. ESI MS m/z 535[C₂₇H₃₀N₆O₄S+H]⁺.

Example 153-[4-(6-amino-pyridin-3-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

2-Amino-4-bromopyridine (Aldrich; 500 mg, 2.89 mmol), (PhCN)₂PdCl₂ (66mg, 0.17 mmol), (t-Bu)₃P.BF₄ (101 mg, 0.345 mmol), and CuI (28 mg, 0.15mmol) under N₂, were added 10 mL of dioxane, 1.02 mL (7.03 mmol) ofMe₃SiCCH, and 0.49 mL (3.5 mmol) of i-Pr₂NH. The mixture was heated to80° C. under and N₂ atmosphere overnight. The mixture was then dilutedwith EtOAc and filtered through Celite. The filtrate was washed withNH₄Cl and brine. The organic phase was dried with Na₂SO₄, filtered, andconcentrated. The dark-brown residue was crystallized from hexanes toprovide 2-amino-4-(trimethylsilyl)ethynyl pyridine (157 mg, 1.88 mmol,65%). ESI MS m/z 191 [C₁₀H₁₄N₂Si+H]⁺. The above trimethylsilylalkyne(340 mg, 1.79 mmol) was dissolved in 3.6 mL of cold THF and 3.6 mL of1.0 M TBAF in THF was slowly added to the stirring mixture. After 2 h,the mixture was concentrated and partitioned between Et₂O and water. Theether layer was washed with brine, and the washes were extracted oncewith Et₂O. The extracts were combined, dried with MgSO₄, filtered, andconcentrated to provide 191 mg of 2-amino-5-ethynyl pyridine (1.61 mmol,91%).

3-Azido-4-methyl benzoic acid (240 mg, 1.24 mmoL) was suspeneded in 3 mLof CH₂Cl₂ and 3 mL of THF. Oxalyl choride (0.14 mL, 1.5 mmol) was added,followed by 1 drop of 10% DMF in THF. The mixture was stirred for 1 hand then concentrated.

The residue was redissolved in dry CH₂Cl₂ (5mL) and 391 mg (1.27 mmol)of N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide wasadded followed by 0.4 ml (2.5 mmol) of DIPEA. The mixture becamehomogeneous, and was stirred for 4 h, and then was washed with 1M NaHSO₄and saturated NaHCO₃. The washes were extracted once with CH₂Cl₂ and theextracts were combined, dried with Na₂SO₄, filtered, and concentrated toprovide 516 mg (93%) of3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideas a tan powder.

To a stirring suspension of 310 mg (0.719 mmol) of3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein 2 mL of EtOH and 2 mL of water was added dropwise 4M NaOH until themixture became homogeneous. A solution of 142 mg (0.719 mmol) of sodiumascorbate in 0.5 mL of water was added, followed by 100 mg (0.719 mmol)2-amino-4-ethynyl pyridine in 1 mL of EtOH. Finally 0.72 mL of 0.1 MCuSO₄ was added, and the resulting mixture was stirred vigorously for 14h. The mixture was then diluted with 40 mL of water and HOAc was addeduntil a precipitate formed and the pH was about 6. The precipitate wasfiltered and washed with water and hexanes. The solids werechromatographed (0-5% MeOH/0.5% NH₄OH in CH₂Cl₂) to provide 321 mg(0.584 mmol; 81%) of the title compound. ESI MS m/z 548[C₂₇H₃₁N₇O₄S—H]⁻.

Example 16N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzamide

3-Azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-benzamidewas prepared from 3-azido benzoic acid andN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in thesame manner as3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide(Example 15). 3-Azido benzoic acid was prepared from 3-amino benzoicacid in the same manner as 3-azido-4-methyl benzoic acid.

Example 16 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-benzamideand 3-ethynyl pyridine in the same manner as Example 15. ESI MS m/z 521[C₂₆H₂₈N₆O₄S+H]⁺.

Example 17N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-4-yl-[1,2,3]triazol-1-yl)-benzamide

Example 17 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 4-ethynyl pyridine hydrochloride (Aldrich) in the same manner asExample 15. ESI MS m/z 535 [C₂₇H₃₀N₆O₄S+H]⁺.

Example 18N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

Example 18 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 5-ethynyl-1-methyl-1H-imidazole (Aldrich) in the same manner asExample 15. ESI MS m/z 538 [C₂₆H₃₁N₇O₄S+H]⁺.

Example 19N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-methylamino-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide

To a solution of 2-methylaminopyridine (Aldrich; 1.00 g, 9.25 mmol) in10 mL of 1:1 HOAc and water was added 2.35 g (9.25 mmol) of I₂. Theresulting brown solution was heated to 80° C. for 3 h. After cooling toroom temperature, the mixture was neutralized with saturated NaHCO₃ andextracted with Et₂O. The extract was washed with water and brine, driedwith MgSO₄, filtered, and concentrated to provide 540 mg of(5-iodo-pyridin-2-yl)-methyl-amine.

(5-Ethynyl-pyridin-2-yl)-methyl-amine was prepared from(5-iodo-pyridin-2-yl)-methyl-amine in the same manner as2-chloro-5-ethynyl-pyridine (Example 1).

Example 19 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand (5-ethynyl-pyridin-2-yl)-methyl-amine in the same manner as Example15. ESI MS m/z 564 [C₂₈H₃₃N₇O₄S+H]⁺.

Example 20N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(4-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide

3-Ethynyl-4-methyl-pyridine was prepared from 3-bromo-4-methyl-pyridinein the same manner as 2-amino-3-ethynyl pyridine (Example 15).

Example 20 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 3-ethynyl-4-methyl-pyridine in the same manner as Example 15. ESI MSm/z 549 [C₂₈H₃₂N₆O₄S+H]⁺.

Example 21N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-fluoro-4-methyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzamide

3-Azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-5-fluoro-4-methyl-benzamidewas prepared from 3-azido-5-fluoro-4-methyl benzoic acid (U.S. Ser. No.04/102492) andN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in thesame manner as3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide(Example 15).

Example 21 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-5-fluoro-4-methyl-benzamideand 3-ethynyl-pyridine in the same manner as Example 15. ESI MS m/z 553[C₂₇H₂₉FN₆O₄S+H]⁺.

Example 22N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-methoxy-pyridin-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

5-Ethynyl-2-methoxy pyridine was prepared from5-bromo-2-methoxy-pyridine (Aldrich) in the same manner as2-chloro-5-ethynyl-pyridine (Example 1).

Example 22 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 5-ethynyl-2-methoxy-pyridine in the same manner as Example 15. ESIMS m/z 565 [C₂₈H₃₂N₆O₅S+H]⁺.

Example 23N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

5-Ethynyl-3-methoxy pyridine was prepared from5-bromo-3-methoxy-pyridine (Frontier) in the same manner as2-chloro-5-ethynyl-pyridine (Example 1).

Example 23 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 5-ethynyl-3-methoxy-pyridine ()in the same manner as Example 15. ESIMS m/z 565 [C₂₈H₃₂N₆O₅S+H]⁺.

Example 24N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-dimethylamino-pyridin-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

To a solution of 2-amino-5-iodopyridine (1.00 g; 4.55 mmol) in 10 mL ofDMF was added 545 mg of 60% NaH (13.6 mmol) and 0.85 mL of iodomethane(13.6 mmol). The mixture was stirred for 14 h, and the mixture wasneutralized with 1M HOAc. The mixture was extracted with Et₂O, theextract was washed with water and brine, dried with MgSO₄, filtered, andconcentrated. Chromatography (0-25% EtOAc in hexanes) provided 700 mg(2.82 mmol) of (5-iodo-pyridin-2-yl)-dimethyl-amine.

(5-Ethynyl-pyridin-2-yl)-dimethyl-amine was prepared from(5-iodo-pyridin-2-yl)-dimethyl-amine in the same manner as2-chloro-5-ethynyl-pyridine (Example 1).

Example 24 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand (5-ethynyl-pyridin-2-yl)-dimethyl-amine in the same manner asExample 15. ESI MS m/z 578 [C₂₉H₃₅N₇O₄S+H]⁺.

Example 25N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-methylsulfanyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

To a mixture of 2.65 g (11.4 mmol) of 1,2-dimethyl-isothioureahydroiodide and 1.00 g (10.4 mmol) of 2-bromo-3-isopropoxy-propenal 8 mLof MeCN was added 1.58 g (11.4 mmol) of K₂CO₃ (Shilcrat, S. C. et al. J.Org. Chem., 1997, 62, 8449-8454). The mixture was stirred at 35° C.under N₂ for 16 h, water (20 ml) was added, and the mixture wasextracted with CH₂Cl₂ (200 mL). The extract was dried over MgSO₄,filtered, concentrated, and chromatographed (0 to 100% EtOAc in hexanes)to provide 1.09 g of3-methyl-2-methylsulfanyl-3H-imidazole-4-carbaldehyde and 284 mg of1-methyl-2-methylsulfanyl-1H-imidazole-4-carbaldehyde.

To a mixture of 850 mg (5.44 mmol) of3-methyl-2-methylsulfanyl-3H-imidazole-4-carbaldehyde and 1.34 g (7.00mmol) of dimethyl 2-oxo-1-diazopropylphosphinate in 15 mL of MeOH wasadded 1.52 g (11.0 mmol) of K₂CO₃. The mixture was stirred at roomtemperature for 28 hours. The mixture was diluted with saturated K₂CO₃(10 mL) and and extracted with CH₂Cl₂ (3×75 mL). The combined extractswere dried over MgSO₄, concentrated, and chromatographed (0 to 100%EtOAc in hexanes) to give the5-ethynyl-1-methyl-2-methylsulfanyl-1H-imidazole (600 mg, 72%) as acolorless liquid.

Example 25 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 5-ethynyl-1-methyl-2-methylsulfanyl-1H-imidazole in the same manneras Example 15. ESI MS m/z 584 [C₂₇H₃₃N₇O₄S+H]⁺.

Example 26N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-cyclopropylamino-pyridin-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

Cyclopropyl-(5-ethynyl-pyridin-2-yl)-amine was prepared fromcyclopropyl-(5-iodo-pyridin-2-yl)-amine in the same manner as2-chloro-5-ethynyl-pyridine (Example 1).Cyclopropyl-(5-iodo-pyridin-2-yl)-amine was prepared from2-chloro-5-iodo-pyridine and cyclopropyl amine in the same manner ascyclopropylmethyl-(5-iodo-pyridin-2-yl)-amine (Example 2).

Example 26 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand cyclopropyl-(5-ethynyl-pyridin-2-yl)-amine in the same manner asExample 15. ESI MS m/z 590 [C₃₀H₃₅N₇O₄S+H]⁺.

Example 27N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-1-methyl-ethyl)-3-methyl-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

Ethyl chloroformate (1.19 mL, 12.4 mmol) in MeCN (5 mL) was addeddropwise to a 1.00 g (6.21 mmol) of 5-bromo-1-methyl-1H-imidazole(Aldrich) in 30 mL of MeCN under N₂. The mixture was stirred and allowedto warm to rt overnight. The mixture was concentrated and the residuewas treated with 2M NaOH (100 mL) and extratcted with CH₂Cl₂ (3×100 mL).The combined extracts were washed with brine, dried with MgSO₄,filtered, concentrated, and chromatographed (0-50% EtOAc in hexanes) togive the 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester asa yellow oil (800 mg).

To a solution of 800 mg (3.43 mmol) of5-bromo-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester in Et₃N (10mL) and THF (10 mL) was added 33 mg (0.17 mmol) of CuI and 120 mg (0.10mmol) of Pd(PPh₃)₄ . Trimethylsilylacetylene (0.48 mL, 3.4 mmol) wasthen added and the reaction was heated at 70° C. under N₂. After 12 h,the mixture was cooled and filtered though a pad of celite, and thenconcentrated and chromatographed (0-50% EtOAc in hexanes) to give1-methyl-5-trimethylsilanylethynyl-1H-imidazole-2-carboxylic acid ethylester as a brown oil (205 mg).

A solution of 0.67 mL of 3M MeMgBr in ether (2.0 mmol) was added to astirring 0° C. solution of 200 mg of1-methyl-5-trimethylsilanylethynyl-1H-imidazole-2-carboxylic acid ethylester (0.80 mmol) in 5 mL of THF over 15 min. The mixture was allowed towarm to rt and stirred overnight. Water (20 mL) was added and themixture was extracted with EtOAc (3×100 mL). The combined extracts werewashed with brine and dried with MgSO₄, filtered, concentrated andchromatographed (10-100 EtOAc in hexanes) to give2-(1-methyl-5-trimethylsilanylethynyl-1H-imidazol-2-yl)-propan-2-ol as ayellow oil (110 mg).

To 2-(1-Methyl-5-trimethylsilanylethynyl-1H-imidazol-2-yl)-propan-2-ol(100 mg, 0.42 mmol) in 5 mL of THF was added IM TBAF in THF (1.3 mL, 1.3mmol). The reaction was stirred at rt overnight, and then was dilutedwith 50 mL of water and extracted with EtOAc (3×50 mL). The combinedextracts were washed with brine and dried with MgSO₄, filtered, andconcentrated to provide 58 mg of2-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-propan-2-ol.

Example 27 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 2-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-propan-2-ol in the samemanner as Example 15. ESI MS m/z 596 [C₂₉H₃₇N₇O₅S+H]⁺.

Example 28N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

Example 28 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand cyclopropylmethyl-(5-trimethylsilanyl-ethynyl-pyridin-2-yl)-amine inthe same manner as Example 15. ESI MS m/z 604 [C₃₁H₃₇N₇O₄S+H]⁺.

Example 29N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-morpholin-4-yl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

4-(1-Methyl-1H-imidazol-2-yl)-morpholine (Nagarajan, K. et al. Indian J.Chem. Sect. B, 21, 10, 1982, 949-952) (1.02 g, 6.08 mmol) was dissolvedin 35 mL of 1,4-dioxane under and N₂ atmosphere. The mixture was heatedto 60° C. and a solution of 0.34 mL (6.4 mmol) of Br₂ in 10 mL ofdichloroethane was added slowly. The mixture was heated for 1 h, thencooled. The mixture was concentrated and the residue was partitionedbetween 6.5 mL of 1 N NaOH and 25 mL of EtOAc. The NaOH solution wasextracted twice more with EtOAc, and the extracts were washed withNaHCO₃ and brine, dried with Na₂SO₄, filtered, concentrated, andchromatographed (0-4% MeOH (0.5% NH₄OH) in CH₂Cl₂) to provide 464 mg of4-(5-bromo-1-methyl-1H-imidazol-2-yl)-morpholine.

4-(5-Ethynyl-1-methyl-1H-imidazol-2-yl)-morpholine was prepared from4-(5-bromo-1-methyl-1H-imidazol-2-yl)-morpholine in the same manner as2-chloro-5-ethynyl-pyridine (Example 1).

Example 29 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 4-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-morpholine in the samemanner as Example 15. ESI MS m/z 623 [C₃₀H₃₈N₈O₅S+H]⁺.

Example 30N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(2,2-dimethyl-propionyl)-3-methyl-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

Preparation of1-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-2,2-dimethyl-propan-1-one wasprepared from 5-bromo-1-methyl imidazole and pivaloyl chloride in thesame manner as 1-methyl-5-ethynyl-1H-imidazole-2-carboxylic acid ethylester (Example 27).

Example 30 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 1-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-2,2-dimethyl-propan-1-one inthe same manner as Example 15. ESI MS m/z 622 [C₃₁H₃₉N₇O₅S+H]⁺.

Example 30N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butylsulfanyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

A 1.6 M solution of n-BuLi in hexanes (16.2 ml; 25.9 mmol) was addedover the course of 5 minutes to 2.06 g (25.9 mmol) of1-methyl-1H-imidazole in 100 mL of THF at −78° C. After stirring for 30minutes, 5.00 mL (25.9 mmol) of t-butyldisulfide was added and reactionwas warmed to rt and stirred for 30 min. The solution was cooled to −78°C. and an additional 16.2 mL (25.9 mmol) of n-BuLi was added over 5minutes. The mixture was stirred cold for 1 h when 6.57g (25.9 mmol) ofI₂ was added. The mixture was warmed to rt and stirred for 15 minutes.Saturated NaHSO₃ (20 mL) was added and mixture was extracted with ether(4×100 mL). The extracts were combined and dried over MgSO₄, filtered,concentrated, and chromatographed (O to 40% EtOAc in hexanes) to give2-tert-butylsulfanyl-5-iodo-1-methyl-1H-imidazole as a tan semi-solid(421 mg).

2-tert-Butylsulfanyl-5-iodo-1-methyl-1H-imidazole was prepared from2-tert-butylsulfanyl-5-iodo-1-methyl-1H-imidazole in the same manner as2-chloro-5-ethynyl-pyridine (Example 1).

Example 30 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 2-tert-butylsulfanyl-5-ethynyl-1-methyl-1H-imidazole in the samemanner as Example 15. ESI MS m/z 626 [C₃₀H₃₉N₇O₄S₂+H]⁺.

Example 32N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-5-methoxy-pyridin-3-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

A mixture of 2.00 g (13.9 mmol) of 2-chloro-3-methoxypyridine(Lancaster) in 13.3 mL of aminomethylcyclopropane was heated at 125° C.in a sealed tube for 4 days. The mixture was then cooled to roomtemperature and partitioned between Et₂O and water. The aqueous layerwas washed with Et₂O, and the combined extracts were washed with brine,dried with MgSO₄, filtered, and concentrated. The residue was passedthrough a plug of silica gel with CH₂Cl₂ to provide 1.25 g (7.01 mmol;50%) of 2-cyclopropylmethylamino-3-methoxypyridine. To a mixture of2-cyclopropyl-methylamino-3-methoxypyridine (430 mg; 2.41 mmol) in 7.5mL of 2:1 HOAc and water was added 612 mg (2.41 mmol) of I₂. The mixturewas heated to 100° C. for 4 h, and an additional 320 mg of I₂ was added.The mixture was heated for 2 h, then cooled to room temperature andstirred for 12 h. Saturated NaHCO₃ (20 mL) and water (20 mL) were addedand the suspension was extracted with EtOAc. The extract was then washedwith 10% Na₂S₂O₃, water, and brine, dried with MgSO₄, filtered, andconcentrated. The pure fractions from chromatography (1-4% MeOH inCH₂Cl₂) were concentrated to provide 145 mg of2-cyclopropylmethylamino-3-methoxy-5-iodopyridine.

To a mixture of 2-cyclopropylmethylamino-3-methoxy-5-iodopyridine (145mg; 0.477 mmol), (Ph₃P)₂PdCl₂ (17 mg; 0.024 mmol), and CuI (5 mg; 0.02mmol) under N₂ was added 2 mL of Et₃N and 75 μL of Me₃SiCCH (0.525mmol). The resulting green suspension was stirred for 30 min at 50° C.The mixture was cooled to room temperature and partitioned between EtOAcand water. The organic extract was washed with water, washed with brine,dried with MgSO₄, filtered, and concentrated. Chromatography (0-1% MeOHin CH₂Cl₂) provided 130 mg of2-cyclopropanemethylamino-3-methoxy-5-(trimethylsilyl)ethynylpyridinecontaminated with a small amount of Ph₃P.

Example 32 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand2-cyclopropanemethylamino-3-methoxy-5-(trimethylsilyl)ethynylpyridine inthe same manner as Example 15. ESI MS m/z 634 [C₃₂H₃₉N₇O₅S+H]⁺.

Example 333-{4-[2-(Hydroxy-phenyl-methyl)-3-methyl-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

(5-Ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone was prepared from5-bromo-1-methyl imidazole and benzoyl chloride in the same manner as1-methyl-5-ethynyl-1H-imidazole-2-carboxylic acid ethyl ester (Example27).

A solution of 200 mg (0.951 mmol) of(5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone in 1 mL of MeOHwas added dropwise to a 0° C. solution of 54 mg (1.43 mmol) of NaBH₄ in5 mL of MeOH. After stirring for 2 h, 10 mL of water was added and themixture was extracted with CH₂Cl₂ (3×50 mL). The combined extracts werewashed with brine, dried with MgSO₄, filtered, concentrated, andchromatographed (0-80% EtOAc in hexanes) to give(5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanol as a white solid(75 mg).

3-Azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamidewas prepared from 3-azido-4-methyl benzoic acid andN-[3-amino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-methanesulfonamidein the same manner as3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide(Example 15).

Example 33 was prepared from3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamideand 5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanol in the samemanner as Example 15. ESI MS m/z 642 [C₃₃H₃₅N₇O₅S+H]⁺.

Example 343-[4-(2-Benzoyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 34 was prepared from(5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone (Example 33) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 15. ESI MS m/z 640[C₃₃H₃₃N₇O₅S+H]⁺.

Example 353-[4-(2-Benzoyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

Example 35 was prepared from(5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone (Example 33) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 15. ESI MS m/z 642 [C₃₃H₃₅N₇O₅S+H]⁺.

Example 363-[4-(2-Benzenesulfonyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

1-Methylimidazole (4.0 mL, 50.3 mmol) was dissolved in dry THF (250 mL)under a N₂ atmosphere. The solution was cooled to −78° C. and n-BuLi(2.5 M in hexanes, 20.1 mL, 50.3 mmol) was added slowly. After 15 minphenyl disulfide (11.0 g, 50.3 mmol) was added and the reaction waswarmed to room temperature and stirred for 30 min. The reaction was thencooled to −78° C. and a second portion of n-BuLi (20.1 mL, 50.3 mmol)was added. After 30 min, iodine (13.4 g, 50.3 mmol) was added. Thereaction was warmed to room temperature and Et₂O (400 mL) and 1 M sodiumbisulfite (250 mL) was added. The layers were separated and the organiclayer washed with brine, dried over MgSO₄, and filtered. The solutionwas concentrated and hexanes were added to the resulting precipitate.The precipitate was collected by vacuum filtration, washed with hexanes,and dried under vacuum to provide5-iodo-1-methyl-2-phenylsulfanyl-1H-imidazole (4.0 g, 25%) as a whitesolid: ESI MS m/z 317 [C₁₀H₉IN₂S+H]⁺.

5-Iodo-1-methyl-2-phenylsulfanyl-1H-imidazole (2.0 g, 6.3 mmol) wasdissolved in CH₂Cl₂ (50 mL). m-CPBA (2.8 g, 12.6 mmol) was added and thereaction stirred for 1 h during which time a white precipitate formed.An additional portion of m-CPBA (1.0 g) was added and the reactionstirred 1 h. Saturated NaHCO₃ was added and the layers were separated.The aqueous layer was extracted with CH₂Cl₂ and the combined extractswere washed with saturated NaHCO₃ and brine, dried over Na₂SO₄,filtered, and concentrated. The residue was dissolved in MeOH (60 mL)with a small amount of CH₂Cl₂. The mixture was boiled until homogeneous,allowed to cool to room temperature and then cooled in ice. Theresulting needles were collected by vacuum filtration, washed with MeOHand hexanes, and then dried under vacuum to providebenzenesulfonyl-5-iodo-1-methyl-1H-imidazole (1.23 g, 56%) as a whitesolid.

2-benzenesulfonyl-5-ethynyl-1-methyl-1H-imidazole was prepared from2-benzenesulfonyl-5-iodo-1-methyl-1H-imidazole in the same manner as2-chloro-5-ethynyl pyridine (Example 1).

Example 36 was prepared from3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideand 2-benzenesulfonyl-5-ethynyl-1-methyl-1H-imidazole in the same manneras Example 15. ESI MS m/z 678 [C₃₂H₃₅N₇O₆S+H]⁺.

Example 37N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino-ethylamino)-pyridin-3-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

To a suspension of Example 1 (100 mg; 0.176 mmol), Pd₂dba₃ (13 mg; 0.014mmol), and t-BuOK (68 mg; 0.70 mmol) in 1.5 mL of toluene stirring underN₂ was added N,N-dimethylaminoethylamine (31 mg; 0.35 mmol) and2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (9.0mg; 0.026 mmol). The resulting suspension was heated to 100° C. for 14h. The reaction was then cooled to room temperature and partitionedbetween EtOAc and water. The layers were separated, with the organicportion being washed twice with water and once with brine. The solutionwas dried with MgSO₄, filtered, and concentrated. The pure fractionsisolated from chromatography (2-7% MeOH (0.5% NH₄OH in CH₂Cl₂) werecombined and concentrated to provide 10 mg of Example 37. ESI MS m/z 621[C₃₁H₄₀N₈O₄S+H]⁺.

Example 38N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzamide

Butyllithium (3.75 mL, 9.40 mmol) and TMEDA (2.24 mL, 14.85 mmol) werestirred at −20° C. in hexanes (7 mL) in an ethanol/dry ice/water bathfor 30 minutes. 1-Methylimidazole (0.5 mL, 6.27 mmol) was added and themixture stirred at room temperature for 1 h. After cooling to −20° C.,Bu₃SnCl (1.70 mL, 15.67 mmol) was added dropwise. The reaction stirredfor 15 minutes at −20° C. then at room temperature overnight beforebeing quenched with 1:1 EtOAc/water (20 mL). The layers were separatedand the aqueous layer extracted with EtOAc (3×). The combined organicswere washed with water, dried over Na₂SO₄, concentrated, andchromatographed (4:96 MeOH/EtOAc) to give1-methyl-5-tributylstannanyl-1H-imidazole (0.486 g).

A solution of 3-hydrazino-4-methyl benzoic acid (See U.S. provisionalapplication 60/570,284) (1.0 g, 4.93 mmol),malonaldehyde(bismethylacetate) (0.82 mL, 4.93 mmol), and concentratedHCl (1 mL) in EtOH (20 mL) was heated to reflux for 4 h. After coolingto room temperature, the reaction was poured into ice water, neutralizedwith 2N NaOH, and extracted with CH₂Cl₂ (3×). The organic layers weredried over Na₂SO₄, filtered and concentrated to afford4-methyl-3-pyrazol-1-yl-benzoic acid ethyl ester (536 mg, 47%) as ayellow oil. A solution of the pyrazole (536 mg, 2.33 mmol) and bromine(0.167mL, 3.26 mmol) in CHCl₃ (15 mL) was refluxed for 4.5 h then cooledand concentrated. Chromatography (1:1 EtOAc/hexanes) yielded3-(4-bromo-pyrazol-1-yl)-4-methyl-benzoic acid ethyl ester (0.739 g,99%). The bromopyrazole (366 mg, 1.18 mmol) was dissolved in dioxane (2mL) and flushed with N₂. 1-Methyl-5-tributylstannanyl-1H-imidazole (366mg, 0.986 mmol) was added to the reaction flask in dioxane (0.5 mL) thenthe flask was purged with N₂. After Pd(PPh₃)₄ (85 mg, 0.074 mmol) wasadded, the reaction was heated to 100° C. in a sealed tube. The reactionmixture was stirred with a 10% KF solution for 30 min then diluted withEtOAc. The layers were separated and the aqueous layer extracted withEtOAc (3×). The organic layers were combined, dried over Na₂SO₄, andconcentrated. The resulting residue was purified by chromatography onsilica gel (5% MeOH/CH₂Cl₂) to give4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzoic acidethyl ester (81 mg, 22%).

A solution ofN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (81 mg,0.261 mmol) in THF (4 mL) was stirred in a bath cooled to −78° C., andn-BuLi (0.22 mL, 0.548 mmol) was added slowly. The cold bath wasremoved, and the reaction was allowed to stir for 30 min. LHMDS (0.261mmol) was then added slowly. The suspension was transferred dropwise toa stirring solution of compound4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzoic acidethyl ester (81 mg, 0.261 mmol) in THF at 0° C. After 30 min cole MeOHwas added and the mixture was partitioned between saturated NH₄Cl andEtOAc, then extracted with EtOAc (3×). The organic combined extractswere washed with brine, dried over Na₂SO₄, filtered, and concentrated,and chromatographed (1% MeOH (with 5% NH₄OH)/CH₂Cl₂ to 5% MeOH (with 5%NH₄H)/CH₂Cl₂) to affordN-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzamide(47 mg, 33%) as an orange foam: ESI MS m/z=537 [C₂₇H₃₂N₆O₄S+H]⁺.

Example 39N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-(4-furan-3-yl-[1,2,3]triazol-1-yl)-4-methyl-benzamide

To a solution of 96 mg (0.20 mmol) of furan-3-carbaldehyde (Aldrich) anddimethyl 2-oxo-1-diazopropylphosphinate (46 mg; 0.24 mmol) in 1.5 mL ofMeOH was added 55.6 mg (0.402 mmol) of K₂CO₃. The mixture was stirredfor 4 h and 58 mg (0.134 mmol) of3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidewas then added followed by an additional 1 mL of MeOH and 27 mg ofsodium ascorbate in 0.2 mL of water. The mixture was vigorously stirredand 0.13 mL (0.013 mmol) of 0.1 M CuSO₄ was added. The head space waspurged with N₂, and the vessel was sealed for 20 h. The mixture was thenpartitioned between EtOAc and 1M HCl, and the extract was washed withsaturated NaHCO₃ and brine. The extract was then dried with Na₂SO₄,filtered, concentrated, and chromatographed (10-50% EtOAc in hexanes) toprovide 57 mg (0.11 mmol; 81%) of Example 39. ES MS m/z 524[C₂₆H₂₉N₅O₅S+H]⁺.

Example 40N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(tetrahydro-furan-3-yl)-[1,2,3]triazol-1-yl]-benzamide

Example 40 was prepared from tetrahydro-furan-3-carbaldehyde (Aldrich)and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS )/z 528 [C₂₆H₃₃N₅O₅S+H]⁺.

Example 41N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyrimidin-5-yl-[1,2,3]triazol-1-yl)-benzamide

Example 41 was prepared from pyrimidine-3-carbaldehyde (Matrix) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 536 [C₂₆H₂₉N₇O₄S+H]⁺.

Example 42N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-thiazol-5-yl-[1,2,3]triazol-1-yl)-benzamide

Example 42 was prepared from thiazole-5-carbaldehyde (Matrix) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 541 [C₂₅H₂₈N₆O₄S₂+H]⁺.

Example 43N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-dimethyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

Example 43 was prepared from 1,5-dimethyl-1H-pyrazole-4-carbaldehyde(Matrix) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 552 [C₂₇H₃₃N₇O₄S+H]⁺.

Example 44N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

Example 44 was prepared from(S)-2,2-dimethyl-[1,3]dioxolane-4-carbaldehyde (Matrix) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 558 [C₂₇H₃₅N₅O₆S+H]⁺.

Example 45N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-cyclopropyl-2-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

Ethyl acetimidate hydrochloride (5.0 g, 40 mmol) and cyclopropylamine(2.3 mL, 40 mL) were dissolved in 45 mL of EtOH and heated to 85° C. ina sealed pressure vessel overnight. The mixture was cooled andconcentrated to provide N-cylcopropyl-acetamidine hydrochloride as aviscous oil. N-Cyclopropyl-acetamidine hydrochloride (1.00 g, 7.43 mmol)and 2-bromo-3-isopropoxy-propenal (Shilcrat, S. C. et al. J. Org. Chem.,1997, 62, 8449-8454) (1.45 g, 7.50 mmol) were dissolved in 13 mL ofCHCl₃ and 1.6 mL of water. Then K₂CO₃ (1.5 g, 11 mmol) was added and themixture was stirred overnight. The reaction was partitioned betweenCH₂Cl₂ (60 mL) and water (30 mL). The layers were separated and theaqueous portion was extracted with CH₂Cl₂ (40 mL). The combined organiclayers were washed with brine (30 mL), dried (MgSO₄), filtered,concentrated, and chromatographed to provide 400 mg of3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde.

Example 45 was prepared from3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 578 [C₂₉H₃₅N₇O₄S+H]⁺.

Example 46N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

In 50 mL of Et₂O were stirred 1.70 g (20.0 mmol) of cyclopropylcarboxamide and 2.9 g (20 mmol) of trimethyloxonium tetrafluoroboratefor 16 h. The resulting suspension was chilled to 0° C., and the etherwas decanted. The solids were washed with 20 mL of cold Et₂O, and theresidue was dried under a stream of N₂. Then 10 mL of EtOH was added,followed by the 2.5 mL of a 33% MeNH₂ solution in EtOH. The reactionvessel was sealed and heated to 80° C. overnight. The mixture was cooledand concentrated to provide 3.7 g of N-methyl-cyclopropanecarboxamidinetetrafluoroborate as a gummy solid.

To a solution of 2.32 g (12.5 mmol) ofN-methyl-cyclopropanecarboxamidine tetrafluoroborate in 4 mL of MeCNwere added 2.41 g (12.5 mmol) of 2-bromo-3-isopropoxy-propenal, 5.1 g(37 mmol) of K₂CO₃, and 0.17 g (0.62 mmol) of 18-crown-6. The mixturewas stirred at rt overnight, and then was concentrated and redissolvedin EtOAc. Water was added to dissolve the salts, the layers wereseparated, and the aqueous phase was extracted twice with EtOAc. Thecombined extracts were washed with a small amount of water and brine,dried over Na₂SO₄, filtered, concentrated, and chromatographed (35-85%EtOAc in hexanes) to provide 646 mg of2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde as a pale yellow oil.

Example 46 was prepared from2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 578 [C₂₉H₃₅N₇O₄S+H]⁺.

Example 47N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

N-methyl-cyclopropanecarboxamidine tetrafluoroborate (0.19 g, 1.0 mmol)and 2-bromo-3-isopropoxy-propenal (Shilcrat, S. C. et al. J. Org. Chem.,1997, 62, 8449-8454) (0.19 g, 1.0 mmol) were dissolved in 1.3 mL ofCHCl₃ and 0.16 mL of water. Then K₂CO₃ (0.45 g, 3.3 mmol) was added andthe mixture was stirred overnight. The reaction was partitioned betweenCH₂Cl₂ and water. The layers were separated and the aqueous portion wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried (MgSO₄), filtered, concentrated, and chromatographed toprovide 0.15 g of a 1:1 mixture of2-cyclopropyl-1-methyl-1H-imidazole-4-carbaldehyde and2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde.

Example 47 was prepared from2-cyclopropyl-1-methyl-1H-imidazole-4-carbaldehyde (as a 1:1 mixturewith 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. Chromatography allowed separation ofExample 47 from Example 46. ESI MS m/z 578 [C₂₉H₃₅N₇O₄S+H]⁺.

Example 48N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide

5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridine-3-carbaldehyde (2:1 with5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridine-2-carbaldehyde) was preparedfrom piperidin-2-ylideneamine hydrochloride (Aldrich) and2-bromo-3-isopropoxy-propenal in the same manner ascyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).

Example 48 was prepared from5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS t/z 578 [C₂₉H₃₅N₇O₄S+H]⁺.

Example 49N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-cyclopropyl-1-isopropyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

3-Cyclopropyl-3-oxo-propionic acid methyl ester (1.25 g, 8.79 mmol) wasdissovled in 6.25 mL of CHCl₃ and 1.17 mL (8.79 mmol) ofdimethylformamide dimethyl acetal was added. The mixture was heated to60° C. in a sealed vessel overnight. The mixuture was then cooled andconcentrated to provide 1.67 g of2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester.

In 10 mL of EtOH was combined 544 mg (2.76 mmol) of2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester, 305 mg(2.76 mmol) of isopropylhydrazine hydrochloride, and 226 (2.76 mmol) ofsodium acetate. The mixture was heated to 60° C. for 12 h. The mixturewas then partitioned between water and EtOAc and the extract was washedwith brine. The washes were extracted twice more with EtOAc and theextracts were combined, dried with Na₂SO₄, filtered, and concentrated toprovide 442 mg of an 85:15 mixture of5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carboxylic acid methyl ester and5-Cyclopropyl-1-isopropyl-1H-pyrazole-3-carbaldehyde.

To an ice-cold solution of5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carboxylic acid methyl ester(442 mg, 2.12 mmol) in THF was slowly added 8.48 mL of 1 M DIBAL-H inCH₂Cl₂. After 2 h 1 mL of EtOAc, was added followed by saturated aqueousNa₂SO₄ with very rapid stirring. After stirring for 10 min, theresulting slurry was diluted with EtOAc until it freely stirred andMgSO₄ was added. The resulting suspension was stirred an additional 30min, and then was filtered through celite. The filter cake was washedwith EtOAc and the combined filtrate was concentrated to provide 337 mgof 5-cyclopropyl-1-isopropyl-1H-pyrazol-4-yl)-methanol.

To a solution of 337 mg (1.87 mmol) of5-cyclopropyl-1-isopropyl-1H-pyrazol-4-yl)-methanol was added 813 mg(9.35 mmol) of activated MnO₂. The slurry was stirred overnight, andthen was filtered through celite (rinsed with CH₂Cl₂) and the filtratewas concentrated to provide an off-white solid. The solid was washedwith with hexanes to provide 170 mg of5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde.

Example 49 was prepared from5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 606 [C₃₁H₃₉N₇O₄S+H]⁺.

Example 50N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

1-Cyclopropyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared withethyl acetoacetate and cylclopropyl hydrazine oxalate (Gever, G. andHayes, K. J. Org. Chem, 1949, 14, 813-818) in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 50 was prepared from1-cyclopropyl-5-methyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 578 [C₂₉H₃₅N₇O₄S+H]⁺.

Example 51N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2,3-diethyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

To 2-ethyl-5-formylimidazole (200 mg; 1.611 mmol) in 2 mL of DMF wasadded 0.132 mL (1.65 mmol) of EtI and 224 mg (1.62 mmol) of K₂CO₃. Themixture was stirred for 12 h, and then it was poured into water andextracted twice with EtOAc. The organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated. Chromatography (0.5-2.0%MeOH in CH₂Cl₂) provided 46 mg (0.30 mmol; 19%) of1,2-diethyl-5-formyl-1H-imidazole and 106 mg (0.69 mmol; 43%) of1,2-diethyl-4-formyl-1H-imidazole.

Example 51 was prepared from 1,2-diethyl-5-formyl-1H-imidazole and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 580 [C₂₉H₃₇N₇O₄S+H]⁺.

Example 52N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,2-diethyl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

Example 52 was prepared from 1,2-diethyl-4-formyl-1H-imidazole (Example51) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 580 [C₂₉H₃₇N₇O₄S+H]⁺.

Example 53N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-isopropyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

2-Isopropyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared fromisobutyramide in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 53 was prepared from2-isopropyl-3-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 580 [C₂₉H₃₇N₇O₄S+H]⁺.

Example 54N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

3-Isopropyl-2-methyl-3H-imidazole-4-carbaldehyde was prepared from ethylacetimidate hydrochloride and isopropylamine in the same manner as3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).

Example 54 was prepared from3-isopropyl-2-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 580 [C₂₉H₃₇N₇O₄S+H]⁺.

Example 55N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

1-Isopropyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared with methylacetoacetate and isopropyl hydrazine hydrochloride in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 55 was prepared from1-isopropyl-5-methyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 580 [C₂₉H₃₇N₇O₄S+H]⁺.

Example 563-[4-(3-tert-Butyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-tert-Butyl-3H-imidazole-4-carbaldehyde was prepared from ethylformimidate hydrochloride (Aldrich) and tert-butylamine in the samemanner as 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example45).

Example 56 was prepared from 3-tert-butyl-3H-imidazole-4-carbaldehydeand3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 580 [C₂₉H₃₇N₇O₄S+H]⁺.

Example 573-{4-[2-(4-Benzyl-piperazin-1-yl)-3-methyl-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideExample 583-{4-[2-(4-Benzyl-piperazin-1-yl)-1-methyl-1H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

To 15 mL of MeCN was added 880 mg (4.99 mmol) of N-benzyl-piperazine and1.16 g (5.00 mmol) of 1,2-dimethyl-isothiourea hydroiodide. The mixturewas heated at reflux overnight. Then, 970 mg (5.02 mmol) of2-bromo-3-isopropoxy-propenal and 2.07 g (15.0 mmol) of K₂CO₃, and 250mg of 18-crown-6 were added and the mixture was heated to refluxovernight. The mixture was cooled, concentrated, and dissolved in EtOAcwith a small amount of water to dissolve salts. The aqueous phase wasextracted twice with EtOAc, and the combined the organics were washedwith water and brine, dried over MgSO₄, concentrated, andchromatographed to provide 250 mg of2-(4-benzyl-piperazin-1-yl)-3-methyl-3H-imidazole-4-carbaldehyde and2-(4-benzyl-piperazin-1-yl)-1-methyl-1H-imidazole-4-carbaldehyde as a1:1 mixture of isomers.

Example 57 and Example 58 were prepared from a mixture of2-(4-benzyl-piperazin-1-yl)-3-methyl-3H-imidazole-4-carbaldehyde and2-(4-benzyl-piperazin-1-yl)-1-methyl-1H-imidazole-4-carbaldehyde in thesame manner as Example 39. The isomers were separated by chromatography(4% EtOH in CH₂Cl₂ with 0.5% NH₄OH).

Example 57: ESI MS m/z 712 [C₃₇H₄₅N₉O₄S+H]⁺.

Example 58: ESI MS m/z 712 [C₃₇H₄₅N₉O₄S+H]⁺.

Example 59N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-dimethylamino-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide Example 60N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-dimethylamino-1-methyl-1H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

2-Dimethylamino-3-methyl-3H-imidazole-4-carbaldehyde and2-dimethylamino-1-methyl-1H-imidazole-4-carbaldehyde were prepared from1,2-dimethyl-isothiourea hydroiodide and dimethylamine in the samemanner as2-(4-benzyl-piperazin-1-yl)-3-methyl-3H-imidazole-4-carbaldehyde and2-(4-benzyl-piperazin-1-yl)-1-methyl-1H-imidazole-4-carbaldehyde(Example 57 and Example 58).

Example 59 and Example 60 were prepared from a mixture of2-dimethylamino-3-methyl-3H-imidazole-4-carbaldehyde and2-dimethylamino-1-methyl-1H-imidazole-4-carbaldehyde in the same manneras Example 39. The isomers were separated by chromatography (4% EtOH inCH₂Cl₂ with 0.5% NH₄OH).

Example 59: ESI MS m/z 581 [C₂₈H₃₆N₈O₄S+H]⁺.

Example 60: ESI MS m/z 581 [C₂₈H₃₆N₈O₄S+H]⁺.

Example 61N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2,3-dihydro-imidazo[2,1-b]thiazol-5-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

2,3-Dihydro-imidazo[2,1-b]thiazole-5-carbaldehyde was prepared from4,5-dihydro-thiazol-2-ylamine and and 2-bromo-3-isopropoxy-propenal inthe same manner as cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde(Example 45).

Example 61 was prepared from 2,3-Dihydro-imidazo[2,1-b]thiazole-5-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 582 [C₂₇H₃₁N₇O₄S₂+H]⁺.

Example 62N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclobutyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

2-Cyclobutyl-3-methyl-3H-imidazole-4-carbaldehyde may be prepared fromcyclobutane carboxamide in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 62 may be prepared from2-cyclobutyl-3-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39

Example 63N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-benzamide

3-Methyl-2-(1-methyl-cyclopropyl)-3H-imidazole-4-carbaldehyde wasprepared from 1-methyl-cyclopropyl carboxamide in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 63 was prepared from3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 592 [C₃₀H₃₇N₇O₄S+H]⁺.

Example 64N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

1-Cyclopropyl-5-ethyl-1H-pyrazole-4-carbaldehyde was prepared with ethyl3-oxopentanoate and cyclopropyl hydrazine oxalate (Gever, G. and Hayes,K. J. Org. Chem, 1949, 14, 813-818) in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 64 was prepared from1-cyclopropyl-5-ethyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 592 [C₃₀H₃₇N₇O₄S+H]⁺.

Example 65N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

5,5-Dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde wasprepared from 5,5-dimethyl-pyrrolidin-2-ylideneamine (Buckley, et al. J.Chem. Soc. 1947, 1507.) and 2-bromo-3-isopropoxy-propenal in the samemanner as cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).

Example 65 was prepared from5,5-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 592 [C₃₀H₃₇N₇O₄S+H]⁺.

Example 66N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

7,7-Dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde maybe prepared from 3,3-dimethyl-pyrrolidin-2-one (Reddy, P. A. et al. J.Med. Chem. 1996, 1898.) and 2-bromo-3-isopropoxy-propenal in the samemanner as cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45)

Example 66 may be prepared from7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39.

Example 67N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

2-tert-Butyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared fromtrimethyl acetamide in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 67 was prepared from2-tert-butyl-3-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 594 [C₃₀H₃₉N₇O₄S+H]⁺.

Example 68N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-tert-butyl-2-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

3-tert-Butyl-2-methyl-3H-imidazole-4-carbaldehyde was prepared fromethyl acetimidate hydrochloride and tert-butylamine in the same manneras 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).

Example 68 was prepared from3-tert-butyl-2-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 594 [C₃₀H₃₉N₇O₄S+H]⁺.

Example 69N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

1-tert-Butyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared with ethylacetoacetate and tert-butyl hydrazine hydrochloride in the same manneras 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 69 was prepared from1-tert-butyl-5-methyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 594 [C₃₀H₃₉N₇O₄S+H]⁺.

Example 70N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-isopropyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

5-Ethyl-1-isopropyl-1H-pyrazole-4-carbaldehyde was prepared with ethyl3-oxopentanoate and isopropyl hydrazine hydrochloride in the same manneras 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 70 was prepared from5-ethyl-1-isopropyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 594 [C₃₀H₃₉N₇O₄S+H]⁺.

Example 71N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-trifluoromethyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide

Example 71 was prepared from 6-trifluoromethyl-pyridine-3-carbaldehyde(Matrix) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 603 [C₂₈H₂₉F₃N₆O₄S+H]⁺.

Example 72N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-(2′-methyl-cycloproane))]-[1,2,3]triazol-1-yl]-benzamide

Spiro[6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-5-(2′-methyl-cyclopropane)]-3-carboxaldehydewas prepared from 1-methyl-4-aza-spiro[2.4]heptan-5-one (Bertus, P.;Szymoniak, J. SYNLEIT, 2, 2003, 265-267) and2-bromo-3-isopropoxy-propenal in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 72 was prepared fromspiro[6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-5-(2′-methyl-cyclopropane)]-3-carboxaldehydeand3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 604 [C₃₁H₃₇N₇O₄S+H]⁺.

Example 73N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-cyclopropyl-2-isopropyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

3-Cyclopropyl-2-isopropyl-3H-imidazole-4-carbaldehyde was prepared fromisobutyramide and cyclopropylamine in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 73 was prepared from3-cyclopropyl-2-isopropyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 606 [C₃₁H₃₉N₇O₄S+H]⁺.

Example 74N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-isopropyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

2-Cyclopropyl-3-isopropyl-3H-imidazole-4-carbaldehyde was prepared fromcyclopropane carboxamide and isopropylamine in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 74 was prepared from2-cyclopropyl-3-isopropyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 606 [C₃₁H₃₉N₇O₄S+H]⁺.

Example 75N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-isopropyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

1-Cyclopropyl-5-isopropyl-1H-pyrazole-4-carbaldehyde was prepared fromethyl 4-methyl-3-oxopentanoate and cyclopropyl hydrazine hydrochloridein the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 75 benzamide was prepared from1-cyclopropyl-5-isopropyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 606 [C₃₁H₃₉N₇O₄S+H]⁺.

Example 76N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-diisopropyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

1,5-Diisoopropyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl4-methyl-3-oxopentanoate and isopropyl hydrazine hydrochloride in thesame manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde(Example 49).

Example 76 was prepared from 1,5-diisoopropyl-1H-pyrazole-4-carbaldehydeand3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 608 [C₃₁H₄₁N₇O₄S+H]⁺.

Example 77N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

Example 77 was prepared from5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (Maybridge) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 614 [C₃₂H₃₅N₇O₄S+H]⁺.

Example 78N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-phenyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

3-Methyl-2-phenyl-3H-imidazole-4-carbaldehyde was prepared from benzenecarboxamide in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 78 was prepared from3-methyl-2-phenyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 614 [C₃₂H₃₅N₇O₄S+H]⁺.

Example 79N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-pyridin-4-yl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

3-Methyl-2-pyridin-4-yl-3H-imidazole-4-carbaldehyde was prepared frompyridine-4-carboxamide in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 79 was prepared from3-methyl-2-pyridin-4-yl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 615 [C₃₁H₃₄N₈O₄S+H]⁺.

Example 80N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

5-Methyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde was prepared fromethyl acetoacetate and 2-pyridyl hydrazine in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 80 was prepared from5-methyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 615 [C₃₁H₃₄N₈O₄S+H]⁺.

Example 81N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[2-methyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-benzamide

2-Methyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazole-4-carbaldehyde wasprepared from ethyl acetimidate hydrochloride and2,2,2-trifluoroethylamine in the same manner as3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).

Example 81 was prepared from2-methyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 620 [C₂₈H₃₂F₃N₇O₄S+H]⁺.

Example 823-[4-(3-tert-Butyl-2-cyclopropyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-tert-Butyl-2-cyclopropyl-3H-imidazole-4-carbaldehyde was prepared fromcyclopropyl carboxamide and tert-butylamine in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 82 benzamide was prepared from3-tert-butyl-2-cyclopropyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 620 [C₃₂H₄₁N₇O₄S+H]⁺.

Example 83N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-methyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

1-Cyclohexyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared from ethylacetoacetate and cyclohexyl hydrazine (TCI) in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 83 was prepared from1-cyclohexyl-5-methyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 620 [C₃₂H₄₁N₇O₄S+H]⁺.

Example 84N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-morpholin-4-yl-thiazol-5-yl)-[1,2,3]triazol-1-yl]-benzamide

Example 84 was prepared from 2-morpholin-4-yl-thiazole-5-carbaldehyde(Bionet) and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 626 [C₂₉H₃₅N₇O₅S₂+H]⁺.

Example 85N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-ethyl-2-phenyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

3-Ethyl-2-phenyl-3H-imidazole-4-carbaldehyde was prepared from benzenecarboxamide and ethylamine in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 85 was prepared from3-ethyl-2-phenyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 628 [C₃₃H₃₇N₇O₄S+H]⁺.

Example 86N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

5-Ethyl-1-phenyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl3-oxo-pentanoate and phenyl hydrazine in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 86 was prepared from 5-ethyl-1-phenyl-1H-pyrazole-4-carbaldehydeand3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 628 [C₃₃H₃₇N₇O₄S+H]⁺

Example 873-[4-(2-Benzyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

2-Benzyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared from2-phenyl-acetamide in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 87 was prepared from2-benzyl-3-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 628 [C₃₃H₃₇N₇O₄S+H]⁺.

Example 88N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

5-Ethyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde was prepared fromethyl 3-oxo-pentanoate and 2-pyridyl hydrazine in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 88 was prepared from5-ethyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS n/z 629 [C₃₂H₃₆N₈O₄S+H]⁺.

Example 89N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-cyclohexane)]-[1,2,3]triazol-1-yl]-benzamide

Spiro[6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-5-cyclohexane]-3-carbaldehydewas prepared from 1-aza-spiro[4.5]dec-2-ylideneamine (Buckley, et al. J.Chem. Soc. 1947, 1507.) and 2-bromo-3-isopropoxy-propenal in the samemanner as cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).

Example 89 was prepared fromspiro[6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-5-cyclohexane]-3-carbaldehydee and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 592 [C₃₀H₃₇N₇O₄S+H]⁺.

Example 90N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(4-fluoro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

Example 90 was prepared from1-(4-fluoro-phenyl)-5-methyl-1H-pyrazole-4-carbaldehyde (Maybridge) and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 632 [C₃₂H₃₄FN₇O₄S+H]⁺.

Example 91N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-ethyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

1-Cyclohexyl-5-ethyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl3-oxo-pentanoate and cyclohexyl hydrazine (TCI) in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 91 was prepared from1-cyclohexyl-5-ethyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 634 [C₃₃H₄₃N₇O₄S+H]⁺.

Example 92N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-methyl-1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-[1,2,3]triazol-1-yl}-benzamide

A solution of 11.2 g (99.0 mmol) of 1-methyl-piperid-4-one and 13.0 g(100 mmol) of Boc-hydrazine in 150 mL of hexanes was refluxed for 30minutes. The hot solution was dried over MgSO₄, filtered, and allowed tocool. The resulting crystals were isolated and recrystallized from Et₂Oto provide 7.2 g of tert-butylN′-(1-Methyl-piperidin-4-ylidene)-hydrazinecarboxylate as a white solid.

A solution of 1 M borane in THF (30 mL) was added to solid 2.80 g (12.3mmol) of tert-butylN′-(1-Methyl-piperidin-4-ylidene)-hydrazinecarboxylate. The mixture wasstirred under N₂ for 16 h when 40 mL of 6M HCl was carefully added. Themixture was heated to 60° C. for 30 min. The mixture was concentrated invacuo at ambient temperature for 2 days. Petroleum ether (200 mL) andpowdered NaOH (5 g) were added, and the mixture was stirred manually for30 min. The mixture was dried with MgSO₄, filtered, and carefullyconcentrated to give 1.3 g of (1-methyl-piperidin-4-yl)-hydrazine.

5-Methyl-1-(1-methyl-piperidin-4-yl)- 1 H-pyrazole-4-carbaldehyde wasprepared from ethyl acetoacetate and (1-methyl-piperidin-4-yl)-hydrazinein the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 92 was prepared from5-methyl-1-(1-methyl-piperidin-4-yl)-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 635 [C₃₂H₄₂N₈O₄S+H]⁺.

Example 93N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

5-Cyclopropyl-1-phenyl-1H-pyrazole-4-carbaldehyde was prepared frommethyl 3-cyclopropyl-3-oxo-propionate and phenyl hydrazine in the samemanner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example49).

Example 93 was prepared from5-cyclopropyl-1-phenyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 640 [C₃₄H₃₇N₇O₄S+H]⁺.

Example 94N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-pyridin-2-yl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

A solution of isopropylmagnesium bromide (2M in Et₂O; 36.5 mL, 73.0mmol) was added to 4.36 mL (36.6 mmol) of malonic acid monoethyl esterin 30 mL of THF under N₂ at 0° C. The reaction was stirred at 0° C. for30 min, at room temperature for 30 min, and then at 40° C. for 30 min.The mixture was subsequently cooled to 0° C. and aimidazol-1-yl-pyridin-2-yl-methanone solution (prepared by stirring 3.00g (24.3 mmol) of pyridine-2-carboxylic acid with 4.7 g (29 mmol) of CDIin 30 mL of THF for 12 h) was slowly added. The reaction was allowed towarm to room temperature and stirred for 12 h. The mixture was thenpoured into ice cold 1M H₃PO₄ (150 mL). Solid NaHCO₃ was added to themixture until the pH reached 7. The mixture was extracted with EtOAc(3×100 mL). The combined organic extracts were washed with NaHCO₃ (100mL) and brine, dried with MgSO₄, filtered, and concentrated to provide2.5 g ethyl 3-oxo-3-pyridin-2-yl-propionate as an oil.

1-Cyclopropyl-5-pyridin-2-yl-1H-pyrazole-4-carbaldehyde was preparedfrom ethyl 3-oxo-3-pyridin-2-yl-propionate and cyclopropyl hydrazineoxalate in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 94 was prepared from1-cyclopropyl-5-pyridin-2-yl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 641 [C₃₃H₃₆N₈O₄S+H]⁺.

Example 953-[4-(3-Benzyl-2-ethyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-Benzyl-2-ethyl-3H-imidazole-4-carbaldehyde and1-benzyl-2-ethyl-1H-imidazole-4-carbaldehyde were prepared in the samemanner as 1,2-diethyl-5-formylimidazole and1,2-diethyl-4-formylimidazole (Example 51).

Example 95 was prepared from3-benzyl-2-ethyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 642 [C₃₄H₃₉N₇O₄S+H]⁺.

Example 963-[4-(1-Benzyl-2-ethyl-1H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

Example 96 was prepared from1-benzyl-2-ethyl-1H-imidazole-4-carbaldehyde (Example 95) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 642 [C₃₄H₃₉N₇O₄S+H]⁺.

Example 97N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

5-Isopropyl-1-phenyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl3-oxo-3-methyl-pentanoate and phenyl hydrazine in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 97 was prepared from5-isopropyl-1-phenyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 642 [C₃₄H₃₉N₇O₄S+H]⁺.

Example 98N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

Example 98 was prepared from1-(4-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbaldehyde (Maybridge) and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 644 [C₃₃H₃₇N₇O₅S+H]⁺

Example 99N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-cyclopropyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

2-Cyclopropyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazole-4-carbaldehyde wasprepared from cyclopropyl carboxamide and 2,2,2-trifluoroethylamine inthe same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde(Example 46).

Example 99 was prepared from2-cyclopropyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 646 [C₃₀H₃₄F₃N₇O₄S+H]⁺.

Example 100N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-phenylsulfanyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

1-Methyl-2-thiophenyl-1H-imidazole (Ohta, S. et al. Bioorg. Med. Chem.Lett. 1992, 40, 2681-2685) (500 mg; 2.63 mmol) was dissolved in 5 mL THFand chilled to −78° C., then n-BuLi (3.29 mL of a 1.6 M solution inhexanes; 5.26 mmol) was added dropwise. The solution was stirred at −78°C. for 15 min, and then a solution of DMF (1.02 mL; 13.1 mmol) in 2 mLTHF was added dropwise. After stirring 10 min, the mixture was warmed toroom temperature. After stirring 1 h, the reaction was quenched withsaturated aqueous NH₄Cl and diluted with EtOAc (30 mL) and water (20mL). The layers were separated and the organic portion was washed withwater (20 mL), brine (20 mL), dried (MgSO₄), filtered, concentrated, andchromatographed (0-5% MeOH in CH₂Cl₂) to provid 458 mg (2.1 0 mmol; 80%)of 1-methyl-2-phenylsulfanyl-1H-imidazole-4-carboxaldehyde.

Example 100 was prepared from1-methyl-2-phenylsulfanyl-1H-imidazole-4-carboxaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 646 [C₃₂H₃₅N₇O₄S₂+H]⁺.

Example 101N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-benzamide

3-Methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazole-4-carbaldehyde wasprepared from 2-phenyl-isobutyramide in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 101 was prepared from3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 656 [C₃₅H₄₁N₇O₄S+H]⁺.

Example 102 3-[4-(2-Benzyloxymethyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

2-Benzyloxymethyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared from2-benzyloxy-acetamide in the same manner as2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).

Example 102 was prepared from2-benzyloxymethyl-3-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 658 [C₃₄H₃₉N₇O₅S+H]⁺.

Example 103N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carbaldehyde was prepared from1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester(Maybridge) in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 103 was prepared from1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 668 [C₃₂H₃₂F₃N₇O₄S+H]⁺.

Example 104N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(1-tert-butyl-piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

To 45.0 g (398 mmol) of 1-methyl-piperid-4-one in 500 mL of acetone wasadded dropwise 60.0 g (423 mmol) of MeI over 1 h. The mixture wasstirred for 3 h, cooled to 0° C., and filtered. The solids were washedwith cold acetone, and dried to provide 1,1-dimethyl-4-oxo-piperidiniumiodide as a pale yellow solid (95.3 g).

A suspension of 64.5 g (253 mmol) of 1,1-dimethyl-4-oxo-piperidiniumiodide in 50 mL of water and 90 mL (860 mmol) of tert-butylamine wasstirred for 15 min when 1.0 mL of 40% Triton B in MeOH was added. Themixture was refluxed for 2 hr under N₂, and then it was extracted withEt₂O (4×100 mL). The aqueous phase was basified with 20 g of NaOH in 20mL of water, and then it was extracted further with Et₂O (4×100 mL). Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered, and concentrated. The residual oil was shaken with 1.5 L ofpetroleum ether, which was decanted and concentrated. The residue wasdistilled under vacuum to provide 1.8 g of 1-tert-butyl-piperid-4-one.

To 1.8 g (11.6 mmol) of 1-tert-butyl-piperid-4-one in 10 mL of hexaneswas added Boc-hydrazine (1.59 g, 12.0 mmol) in 75 mL of hexanes. Themixture was refluxed for 30 minutes, dried hot with MgSO₄, filteredwhile hot, and then concentrated to provide 3.0 g ofN′-(1-tert-Butyl-piperidin-4-ylidene)-hydrazinecarboxylic acidtert-butyl.

A 1M solution borane in THF (28.7 mL, 28.7 mmol) was added toN′-(1-tert-Butyl-piperidin-4-ylidene)-hydrazinecarboxylic acidtert-butyl ester. The mixture was stirred for 16 h, and then 40 mL of 6MHCl was added. The mixture was heated to 60° C. for 30 min. The mixturewas concentrated and 200 mL of petroleum ether was added, followed bypowdered NaOH (5 g). The slurry was stirred manually for 30 min, andthen the mixture was dried with MgSO₄, filtered, and concentrated togive 1.21 g of (1-tert-butyl-piperidin-4-yl)-hydrazine (1.21 g).

1-(1-tert-Butyl-piperidin-4-yl)-5-methyl-1H-pyrazole-4-carbaldehyde wasprepared from ethyl acetoacetate and(1-tert-butyl-piperidin-4-yl)-hydrazine in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

Example 104 was prepared from1-(1-tert-butyl-piperidin-4-yl)-5-methyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 677 [C₃₅H₄₈N₈O₄S+H]⁺.

Example 1053-{4-[2-(1-Benzyloxy-cyclopropyl)-3-methyl-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

1-Hydroxy-cyclopropanecarboxylic acid methyl ester (Acros; 1.00 g, 8.61mmol) in 24 mL of THF was stirred with 516 mg (12.9 mmol) of NaH (60% inmineral oil) for 10 min. Benzyl bromide (1.13 mL, 9.37 mmol) and Bu₄I(0.32 g, 0.85 mmol) were then added, and the mixture was stirredovernight. The mixture was diluted with EtOAc and washed with saturatedNH₄Cl. The wash was extracted once with EtOAc, and the combined extractswere washed with brine, dried with Na₂SO₄, filtered, concentrated, andchromatographed (0-50% EtOAc in hexanes) to provide 774 mg (3.75 mmol)of 1-benzyloxy-cyclopropanecarboxylic acid methyl ester that wasdissolved in 14 mL of 1:1 Is EtOH/THF. Sodium hydroxide (1M, 5.63 mL)was added, and the mixture was stirred for 4 h. After concentrating, 5mL of water was added and the solution was extracted once with Et₂O. Theaqueous layer was then adjusted to pH 3 with HCl, and the suspension wasextracted twice with EtOAc. The extracts were washed with brine, driedwith Na₂SO₄, filtered, and concentrated to provide 723 mg of1-Benzyloxy-cyclopropanecarboxylic acid. To the above acid (3.76 mmol)in 10 mL of CH₂Cl₂ was added 2.82 mL (5.64 mmol) of 2M oxalyl chloridein CH₂Cl₂ and one drop of DMF. After stirring for 15 min, the mixturewas concentrated and redissolved in 4 mL of MTBE and 0.15 mL of CH₂Cl₂and chilled to 0° C. Ammonium hydroxide (28% in water; 0.78 mL) wasadded, and the mixture was stirred for 15 min when 1 mL of saturatedNaHCO₃ was added. The mixture was extracted twice with EtOAc, and theextracts were combined, washed with brine, dried with Na₂SO₄, filtered,and concentrated to provide 550 mg of 1-benzyloxy-cyclopropanecarboxylicacid amide as a yellow oil.

2-(1-Benzyloxy-cyclopropyl)-3-methyl-3H-imidazole-4-carbaldehyde wasprepared from 1-benzyloxy-cyclopropanecarboxylic acid amide in the samemanner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example46).

Example 105 was prepared from2-(1-benzyloxy-cyclopropyl)-3-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 684 [C₃₆H₄₁N₇O₅S+H]⁺.

Example 1063-{4-[2-(2-Benzyloxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

3-Hydroxy-2,2-dimethyl-propionic acid methyl ester (3.00 g, 22.7 mmol)in 40 mL of THF at 0° C. was treated with 1.0 g (25 mmol) of 60% NaH inmineral oil for 20 min. Benzyl bromide (2.97 mL, 25.0 mmol) was addeddropwise over 10 minutes. The mixture was stirred overnight, 30 mL ofwater was added, and the mixture was extracted with EtOAc (3×100 mL).The combined extracts were washed with brine, dried with MgSO₄,filtered, and concentrated. The residue was dissolved in 40 mL of EtOH,28 mL of 2M NaOH was added, and the mixture was heated to 80° C. for 12h. The mixture was cooled, neutralized with 2M HCl, and extracted withEtOAc (3×100 mL). The combined extracts were washed with brine, driedwith MgSO₄, filtered, concentrated, and chromatographed (10-100% EtOAcin hexanes) to provide 2.4 g of 3-benzyloxy-2,2-dimethyl-propionic acid.

To a 0° C. solution of 2.4 g (11.4 mmol) of3-benzyloxy-2,2-dimethyl-propionic acid and 1.65 ml (11.5 mmol) of Et₃Nin 80 mL of chloroform was added 1.04 mL (11.5 mmol) of ethylchloroformate. After stirring for 15 min, NH₃ gas was passed through thesolution for 5 minutes. The resulting suspension was removed from theice bath and allowed to stir overnight. The suspension was filtered andthe filtrate was concentrated to near dryness. The resulting residue wascrystallized from benzene/hexanes (16 mL/40 mL) mixture to provide 2.3 gof 3-benzyloxy-2,2-dimethyl-propionamide.

2-(2-Benzyloxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazole-4-carbaldehydewas prepared from 3-benzyloxy-2,2-dimethyl-propionamide in the samemanner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example46).

Example 106 was prepared from2-(2-benzyloxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazole-4-carbaldehydeand3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 700 [C₃₇H₄₅N₇O₅S+H]⁺.

Example 1073-{4-[1-(1-Benzyl-piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl]-[1,2,3]triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

1-(1-Benzyl-piperidin-4-yl)-5-methyl-1H-pyrazole-4-carbaldehyde wasprepared from ethyl acetoacetate and (1-benzyl-piperidin-4-yl)-hydrazinein the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).(1-Benzyl-piperidin-4-yl)-hydrazine was prepared from1-benzyl-piperidin-4-one in the same manner as(1-methyl-piperidin-4-yl)-hydrazine (Example 92).

Example 107 was prepared from1-(1-benzyl-piperidin-4-yl)-5-methyl-1H-pyrazole-4-carbaldehyde and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 711 [C₃₈H₄₆N₈O₄S+H]⁺.

Example 1084-(4-{1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazol-4-yl}-2-cyclopropyl-2H-pyrazol-3-yl)-piperidine-1-carboxylicacid tert-butyl ester

N-Boc-4-(2-Ethoxycarbonyl-acetyl)-piperidine was prepared fromN-Boc-piperidine-4-carboxylic acid in the same manner as ethyl3-oxo-3-pyridin-2-yl-propionate (Example 94).

N-Boc-4-(2-Cyclopropyl-4-ethoxycarbonyl-2H-pyrazol-3-yl)-piperidine wasprepared from N-Boc-4-(2-ethoxycarbonyl-acetyl)-piperidine andcyclopropyl hydrazine oxalate in the same manner as5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester(Example 49).

A solution of 1.71 mL (3.42 mmol) of 2M NaOH was added to 0.540 g (1.49mmol)N-Boc-4-(2-cyclopropyl-4-ethoxycarbonyl-2H-pyrazol-3-yl)-piperidine in15 mL of EtOH. After stirring at 60° C. for 18 h, the solution wasconcentrated and dissolved in 100 mL of EtOAc (100 mL) and 10 mL of 5%HCl (10 mL). The extract was washed with 50 mL of brine (50 mL), driedover MgSO₄, filtered, concentrated, and chromatographed (0-100% EtOAc inhexanes) to give 330 mg ofN-Boc-4-(4-carboxy-2-cyclopropyl-2H-pyrazol-3-yl)-piperidine as a whitepowder.

The above acid (300 mg, 0.894 mmol) was dissolved in 5 mL of THF. Tothis solution was added 3.58 mL (3.58 mmol) of 1M borane in THF. Afterstirring for 5 h, the mixture was poured into 15 mL of 5% HCl. Thesolution was extracted with 200 mL of EtOAc, and the extract was washedwith saturated NaHCO₃ and brine, dried over MgSO₄, filtered,concentrated, and chromatographed (10-100 EtOAc in hexanes) to give 120mg ofN-Boc-4-(2-cyclopropyl-4-hydroxymethyl-2H-pyrazol-3-yl)-piperidine. Thisalcohol (100 mg, 0.31 mmol) was stirred overnight in 10 mL of THF with270 mg (3.1 mmol) of activated MnO₂. The mixture was filtered andconcentrated to provide 70 mg ofN-Boc-4-(2-cyclopropyl-4-formyl-2H-pyrazol-3-yl)-piperidine.

Example 108 was prepared fromN-Boc-4-(2-cyclopropyl-4-formyl-2H-pyrazol-3-yl)-piperidine and3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 747 [C₃₈H₅₀N₈O₆S+H]⁺.

Example 109[[2-(4-{1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazol-4-yl}-2-phenyl-2H-pyrazol-3-yl)-ethyl]-carbamicacid benzyl ester

Ethyl 5-benzyloxycarbonylamino-3-oxo-pentanoate was prepared fromN-Cbz-β-alanine in the same manner as ethyl3-oxo-3-pyridin-2-yl-propionate (Example 94).

[2-(4-Formyl-2-phenyl-2H-pyrazol-3-yl)-ethyl]-carbamic acid benzyl esterwas prepared from ethyl 5-benzyloxycarbonylamino-3-oxo-pentanoate in thesame manner asN-Boc-4-(2-cyclopropyl-4-formyl-2H-pyrazol-3-yl)-piperidine (Example108).

Example 109 was prepared from[2-(4-formyl-2-phenyl-2H-pyrazol-3-yl)-ethyl]-carbamic acid benzyl esterand3-azido-N-(5-tert-butyl-3-methane-sulfonylamino-2-methoxy-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 777 [C₄₁H₄₄N₈O₆S+H]⁺.

Example 110N-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

3-Azido-N-(5-tert-butyl-2-methoxy-phenyl)-4-methyl-benzamide wasprepared from 3-azido-4-methyl benzoic acid (U.S. Ser. No. 04/102492)and 5-tert-butyl-2-methoxy-phenylamine in the same manner as3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide(Example 15).

Example 110 was prepared from2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46) and3-azido-N-(5-tert-butyl-2-methoxy-phenyl)-4-methyl-benzamide in the samemanner as Example 39. ESI MS m/z 485 [C₂₈H₃₂N₆O₂+H]⁺.

Example 111N-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

3-Azido-N-(5-tert-butyl-3-cyano-2-methoxy-phenyl)-4-methyl-benzamide wasprepared from 3-azido-4-methyl benzoic acid (U.S. Ser. No. 04/102492)and 3-amino-5-tert-butyl-2-methoxy-benzonitrile in the same manner as3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide(Example 15).

Example 111 was prepared from2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46) and3-azido-N-(5-tert-butyl-3-cyano-2-methoxy-phenyl)-4-methyl-benzamide inthe same manner as Example 39. ESI MS m/z 510 [C₂₉H₃₁N₇O₂+H]⁺.

Example 112N-(5-tert-Butyl-2-methanesulfinyl-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

3-Azido-N-(5-tert-butyl-2-methanesulfinyl-phenyl)-4-methyl-benzamide wasprepared from 3-azido-4-methyl benzoic acid (U.S. Ser. No. 04/102492)and 5-tert-butyl-2-methanesulfinyl-phenylamine in the same manner as3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide(Example 15).

Example 112 was prepared from2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46) and3-azido-N-(5-tert-butyl-2-methanesulfinyl-phenyl)-4-methyl-benzamide inthe same manner as Example 39. ESI MS m/z 517 [C₂₈H₃₂N₆O₂S+H]⁺.

Example 113N-(5-tert-Butyl-3-methanesulfonylamino-2-methyl-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamide

3-Azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methyl-phenyl)-4-methyl-benzamidewas prepared from 3-azido-4-methyl benzoic acid (U.S. Ser. No.04/102492) andN-(3-Amino-5-tert-butyl-2-methyl-phenyl)-methanesulfonamide in the samemanner as3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide(Example 15).

Example 113 was prepared from2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46) and3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methyl-phenyl)-4-methyl-benzamidein the same manner as Example 39. ESI MS m/z 562 [C₂₉H₃₅N₇O₃S+H]⁺.

Example 114N-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

Example 114 was prepared from5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (Maybridge) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 612[C₃₂H₃₃N₇O₄S+H]⁺.

Example 1153-[4-(3-tert-Butyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 115 was prepared from 3-tert-butyl-3H-imidazole-4-carbaldehyde(Example 56) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 578[C₂₉H₃₅N₇O₄S+H]⁺.

Example 1163-[4-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 116 was prepared from1-isopropyl-5-methyl-1H-pyrazole-4-carbaldehyde (Example 55) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 578[C₂₉H₃₅N₇O₄S+H]⁺.

Example 1173-[4-(2-Isopropyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 117 was prepared from2-isopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 53) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 578[C₂₉H₃₅N₇O₄S+H]⁺.

Example 1183-[4-(2-Cyclopropyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 118 was prepared from2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 576[C₂₉H₃₃N₇O₄S+H]⁺.

Example 1193-[4-(2-Cyclobutyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 119 may be prepared from2-cyclobutyl-3-methyl-3H-imidazole-4-carbaldehyde and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39.

Example 120N-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-benzamide

Example 120 was prepared from3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazole-4-carbaldehyde (Example63) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 590[C₃₀H₃₅N₇O₄S+H]⁺.

Example 1213-[4-(1-Cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 121 was prepared from1-cyclopropyl-5-ethyl-1H-pyrazole-4-carbaldehyde (Example 64) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 590[C₃₀H₃₅N₇O₄S+H]⁺.

Example 1223-[4-(1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 122 was prepared from1-tert-butyl-5-methyl-1H-pyrazole-4-carbaldehyde (Example 69) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 592[C₃₀H₃₇N₇O₄S+H]⁺.

Example 1233-[4-(3-tert-Butyl-2-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 123 was prepared from3-tert-butyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 68) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 592[C₃₀H₃₇N₇O₄S+H]⁺.

Example 1243-[4-(2-tert-Butyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 124 was prepared from2-tert-butyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 67) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 592[C₃₀H₃₇N₇O₄S+H]⁺.

Example 1253-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 125 was prepared from5-ethyl-1-phenyl-1H-pyrazole-4-carbaldehyde (Example 86) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 626[C₃₃H₃₅N₇O₄S+H]⁺.

Example 1263-[4-(3-Ethyl-2-phenyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

Example 126 was prepared from3-ethyl-2-phenyl-3H-imidazole-4-carbaldehyde (Example 85) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 626[C₃₃H₃₅N₇O₄S+H]⁺.

Example 127N-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazol-4-yl]-[1,2,3]triazol-1-yl}-benzamide

Example 127 was prepared from3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazole-4-carbaldehyde(Example 101) and3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide(Example 33) in the same manner as Example 39. ESI MS m/z 655[C₃₅H₃₉N₇O₄S+H]⁺.

Example 128N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-hydroxymethyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

A mixture of 386 mg (0.587 mmol) of Example 102, 185 mg (2.94 mmol) ofammonium formate, 40 mg of Pd/C in 20 mL MeOH (20 mL) with 0.1 mL (1.2mmol) of formic acid was stirred at rt for 12 h. The mixture wasfiltered through celite and concentrated to provide 280 mg of Example128. ESI MS m/z 568 [C₂₇H₃₃N₇O₅S+H]⁺.

Example 129N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-formyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

Example 128 (400 mg, 0.705 mmol) was dissolved in THF (20 mL) and 308 mgof activated MnO₂ was added. The reaction was stirred for 12 h and wasthen filtered through celite and concentrated. The residue was dissolvedin EtOAc and washed with water and brine, dried with MgSO₄, filtered,concentrated, and chromatographed (10-100% EtOAc in hexanes) to provide200 mg of Example 129. ESI MS m/z 567 [C₂₇H₃₁N₇O₅S+H]⁺.

Example 130N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

To a 0° C. solution of 45 mg (0.080 mmol) of Example 129 in 10 mL of THFwas slowly added 0.11 mL (0.32 mmol) of 3M MeMgBr in Et₂O. The mixturewas allowed to warm to rt with stirring overnight. A 10% HCl solutionwas added, and the mixture was extracted with EtOAc (3×50 mL) and thecombined organics were washed with brine, dried with MgSO₄,concentrated, and chromatographed (0-10% MeOH in CH₂Cl₂) to provideExample 129 (45 mg). ESI MS m/z 582 [C₂₈H₃₅N₇O₅S]⁺.

Example 131N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(cyclopropyl-hydroxy-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

To a 0° C. solution of 50 mg (0.088 mmol) of Example 129 in 5 mL of THFwas slowly added 0.88 mL (0.44 mmol) of cyclopropylmagnesium bromide(0.5 M in THF). The mixture was allowed to warm to rt with stirringovernight. Water (50 mL) was added, and the mixture was extracted withEtOAc (3×50 mL), the combined organics were washed with brine, driedwith MgSO₄, concentrated, and chromatographed (0-10% MeOH in CH₂Cl₂) toprovide Example 131 (15 mg). ESI MS m/z 609 [C₃₀H₃₇N₇O₅S+H]⁺.

Example 1323-[4-(2-Acetyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

To 15 mg (0.026 mmol) of Example 130 in 5 mL of THF was added 7.6 mg(0.13 mmol) of activated MnO₂. The reaction stirred at overnight, thenwas filtered through celite and concentrated to provide 10 mg of Example132. ESI MS m/z 580 [C₂₈H₃₃N₇O₅S+H]⁺.

Example 1333-[4-(2-Cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[5-(2-hydroxy-1,1-dimethyl-ethyl)-3-methanesulfonylamino-2-methoxy-phenyl]-4-methyl-benzamide

A solution of TMSCHCN₂ (1.0 M) was added to 4.28 g (17.3 mmol) of(4-hydroxy-3,5-dinitro-phenyl)-acetic acid in 63 mL of MeCN and 7 mL ofMeOH. After 2h, 0.8 mL of acetic acid was added. After stirring anadditional 30 min, the solution was concentrated and partitioned betweensaturated NaHCO₃ and EtOAc. The organic portion was washed with brine,dried with Na₂SO₄, filtered, and concentrated to provide(4-methoxy-3,5-dinitro-phenyl)-acetic acid methyl ester (3.22 g).

Methyl iodide (3.36 mL, 54.0 mmol) was added to 3.65 g (13.5 mmol) of(4-methoxy-3,5-dinitro-phenyl)-acetic acid methyl ester in 40 mL of DMFat 0° C. Sodium hydride (60%; 1.62 g, 40.5 mmol) was carefully added inportions. The mixture was allowed to warm to rt, then it was dilutedwith water and extracted with EtOAc. The aqueous layer was extractedtwice with EtOAc, and the extracts were washed with water and brine. Theextracts were combined, dried with Na₂SO₄, filtered, and concentrated toprovide a brown oil. Hexanes was added, swirled around the flask, anddecanted. This procedure was repeated twice, and the resulting residuewas dried in vacuo to provide 2.96 g of2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propionic acid methyl ester.

To a 0° C. solution of 1.30 g (4.35 mmol) of2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propionic acid methyl ester in30 mL of THF was added dropwise 17 mL (17 mmol) of 1.0 M DIBAL inCH₂Cl₂. After stirring an additional 4 h, 2 mL of MeOH and thensaturated Na₂SO₄ (2 mL) were slowly added. The resulting suspension wasrapidly stirred for 20 min then 40 mL of EtOAc was added followed byMgSO₄. The resulting mixture was then stirred at rt for an additional 30min. The mixture was filtered through celite, and the filter cake waswashed with EtOAc. The filtrate was concentrated to provide 580 mg of2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propan-1-ol.

2-(4-Methoxy-3,5-dinitro-phenyl)-2-methyl-propan-1-ol was dissolved in 5mL of CH₂Cl₂. Acetic anhydride was added followed by DMAP. The mixturewas stirred overnight, then diluted in 15 mL of CH₂Cl₂ and washed with 1M NaSO₄, saturated NaHCO₃, and brine. The CH₂Cl₂ solution was then driedwith Na₂SO₄, filtered, and concentrated to provide acetic acid2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propyl ester (628 mg) as abrown oil.

Acetic acid 2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propyl ester (625mg, 2.00 mmol) was dissolved in 10 mL MeOH. Ethyl acetate (10 mL),ammonium formate (1.26 g, 20.0 mmol), and Pd/C (56 mg) were added andthe mixture was heated to 40° C. overnight. The mixture was thenfiltered through celite and partitioned between sat'd NaHCO₃ and EtOAc.The EtOAc extract was washed with brine. The washes were extracted oncemore with EtOAc. The extracts were combined, dried with Na₂SO₄,filtered, and concentrated to provide 500 mg of acetic acid2-(3,5-diamino-4-methoxy-phenyl)-2-methyl-propyl ester.

To a solution of 500 mg (1.99 mmol) of acetic acid2-(3,5-diamino-4-methoxy-phenyl)-2-methyl-propyl ester in 10 mL of MTBEwas added 0.16 mL (2.0 mmol) of methansulfonyl chloride and 0.35 mL (2.0mmol) of DIPEA. The mixture was stirred overnight, and then was washedwith saturated NH₄Cl, saturated NaHCO₃, and brine. The ether layer wasdried with Na₂SO₄, filtered, concentrated, and chromatographed (0-2.5%MeOH (0.05% NH₄OH) in CH₂Cl₂) to provide 265 mg of2-(3-amino-5-methanesulfonylamino-4-methoxy-phenyl)-2-methyl-propylester.

Oxalyl chloride (0.11 mL, 1.3 mmol) was added to a stirring suspensionof 148 mg (0.84 mmol) of 3-azido-4-methyl benzoic acid in 5 mL of 1:1CH₂Cl₂/THF followed by 1 drop of 10% DMF in THF. After stirring for 1 h,the now homogeneous mixture was concentrated to provide a dark oil. Theacid chloride was dissolved in 5 mL of CH₂Cl₂ and 185 mg (0.56 mmol) ofacetic acid2-(3-amino-5-methanesulfonylamino-4-methoxy-phenyl)-2-methyl-propylester was added along with 0.2 mL (1.7 mmol) of 2,6-lutidine. Themixture was stirred overnight, then was diluted with 10 mL of CH₂Cl₂,and washed with 1 M NaHSO₄ (2×), saturated NaHCO₃, and brine. Theorganic portion was dried with Na₂SO₄, filtered, and concentrated toprovide acetic acid2-[3-(3-azido-4-methyl-benzoylamino)-5-methanesulfonylamino-4-methoxy-phenyl]-2-methyl-propylester (238 mg).

To a stirring suspension of 49 mg (0.10 mmol) of acetic acid2-[3-(3-azido-4-methyl-benzoylamino)-5-methanesulfonylamino-4-methoxy-phenyl]-2-methyl-propylester in 1 mL of EtOH was added 4N NaOH dropwise until the solidsdissolved. 2-Cyclopropyl-5-ethynyl-1-methyl-1H-imidazole (125 mg, 0.855mmol) was added followed by 20 mg (0.1 mmol) of sodium ascorbate inwater. The mixture was stirred under N₂ and CuSO₄ (0.1 M; 0.1 mL, 0.010mmol) was added. The suspension was stirred overnight, then was wasdiluted with half-saturated NH₄Cl, and extracted with EtOAc. The extractwas washed with brine, and the washes were extract once more wtih EtOAc.The extracts were combined, dried with Na₂SO₄, filtered, andconcentrated. Chromatography (0-4% MeOH (0.5% NH₄OH) in CH₂Cl₂) providedthe desired product with a slight blue-green color. The product was thenredissolved in EtOAc and washed again with NH₄Cl with a few drops ofNH₄OH added. The aqueous layer became blue, and the organic layer waswashed once more with NH₄Cl/NH₄OH, and once with brine. The organiclayer was then dried with Na₂SO₄, filtered, and concentrated to provideExample 133 (83 mg). ESI MS m/z 594 [C₂₉H₃₅N₇O₅S+H]⁺.

Example 134N-[5-(2-Hydroxy-1,1-dimethyl-ethyl)-3-methanesulfonylamino-2-methoxy-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamide

Example 134 was prepared in the same manner as3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[5-(2-hydroxy-1,1-dimethyl-ethyl)-3-methane-sulfonylamino-2-methoxy-phenyl]-4-methyl-benzamide(Example 133) with 1.5 equivalents of5-ethynyl-1-methyl-2-(1-methyl-cyclopropyl)-1H-imidazole. ESI MS m/z 608[C₃₀H₃₇N₇O₅S+H]⁺.

Example 135N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-piperidin-4-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamide

Example 107 (210 mg; 0.30 mmol) and 10% Pd/C (65 mg) were stirred in 6mL of MeOH with 1 g of ammonium formate for 8 h. The mixture was thenfiltered through Celite and concentrated. The resulting residue waspartitioned between water (5 mL) and EtOAc (100 mL). Brine (20 mL) andsaturated NaHCO₃ were added and the organic layer was separated and theaqueous layer was extracted with EtOAc (2×25 mL). The extracts werecombined, washed with brine, dried over MgSO₄, and concentrated to giveExample 135 (125 mg; 68%). ESI MS m/z 621 [C₃₁H₄₀N₈O₄S+H]⁺.

Example 136N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-piperazin-1-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamide

A mixture of Example 57 (100 mg, 0.14 mmol) and 40 mg of Pd(OH)₂ in 10mL of MeOH was stirred under and H₂ atmosphere for 72 h. The mixture wasfiltered through Celite and concentrated to provide Example 136. MS m/z622 [C₃₀H₃₉N₉O₄S+H]⁺.

Example 137N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(1-methyl-2-piperazin-1-yl-1H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-benzamide

Example 137 was prepared from Example 58 in the same manner as Example136. ESI MS m/z 622 [C₃₀H₃₉N₉O₄S+H]⁺.

Example 138N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-cyclopropyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

A solution of 190 mg (0.28 mmol) of Example 105 in 2 mL of EtOH wasstirred over 30 mg of Pd/C under and H₂ atmosphere for 3.5 h.Concentrated HCl (0.027 mL, 0.33 mmol) was added to the mixture, thetemperature was warmed to 40° C., and the mixture was stirred overnight.The mixture was cooled and filtered through celite. The filter cake waswashed with CH₂Cl₂, and the combined filtrates were washed withsaturated NaHCO₃ and brine. The organics were dried with Na₂SO₄,filtered, and concentrated to provide Example 138 (130 mg). ESI MS m/z594 [C₂₉H₃₅N₇O₄S+H]⁺.

Example 139N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-ethyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamideHydrochloride

Example 96 (120 mg; 0.187 mmol) was stirred with 15 mL of MeOH, 4 dropsof concentrated HCl, and 25 mg of Pd/C. The mixture was then stirred for20 h under an H₂ atmosphere at 50° C. The mixture was filtered throughdiatomaceous earth and concentrated. The residue was crystallized fromMeOH/Et₂O to provide 93 mg (0.16 mmol; 85%) of Example 138 as thehydrochloride salt. ESI MS m/z 552 [C₂₇H₃₃N₇O₄S+H]⁺.

Example 139N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfonyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

To Example 25 (250 mg, 0.43 mmol) in 10 mL of MeOH (10 mL) was added 790mg (2.6 mmol) of oxone in 10 mL of water. The mixture was stirred for 16h before being partitioned between CHCl₃ (10 mL) and water (10 mL) with3 mL of NH₄OH. The mixture was extracted with chloroform (3×60 mL),dried over MgSO₄, concentrated, and chromatographed (25 to 100% EtOAc inhexanes) to provide Example 139 (216 mg). ESI MS m/z 616[C₂₇H₃₃N₇O₆S₂+H]⁺.

Example 140N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(2-methyl-propane-2-sulfonyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamide

Example 140 was prepared from Example 30 in the same manner as Example139. ESI MS m/z 658 [C₃₀H₃₉N₇O₆S₂+H]⁺.

Example 141N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfinyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

To Example 25 (410 mg, 0.69 mmol) in 10 mL of MeOH (10 mL) was added 370mg (1.2 mmol) of oxone in 10 mL of water. The mixture was stirred at 0°C. for 22 h before being partitioned between CHCl₃ (10 mL) and water (10mL) with 3 mL of NH₄OH. The mixture was extracted with chloroform (3×60mL), dried over MgSO₄, concentrated, and chromatographed (85 to 100%EtOAc in hexanes) to provide Example 141 (360 mg). ESI MS m/z 601[C₂₇H₃₃N₇O₅S₂+H]⁺.

Example 142N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(hydroxy-phenyl-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

To a solution of 30 mg (0.047 mmol) of Example 35 in 2 mL of EtOH wasadded 7 mg (0.18 mmol) of NaBH₄. After stirring for 2 h, 2 mL of waterwas added and the mixture was extracted with CH₂Cl₂ (3×20 mL). Thecombined organics were washed with brine, dried with MgSO₄, andconcentrated to provide 17 mg of Example 142. ESI MS m/z 645[C₃₃H₃₇N₇O₅S+H]⁺.

Example 143N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-2,2-dimethyl-propyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

Example 143 was prepared from Example 30 in the same manner as Example142. ESI MS m/z 624 [C₃₁H₄₁N₇O₅S+H]⁺.

Example 144N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-piperidin-4-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide

To a solution of Example 108 (50 mg, 0.067 mmol) in 2 mL of MeOH wasadded 2M HCl (5 mL). The mixture was stirred at for 12 h. Solventremoved under vacuum and the resulting residue was dissolved in CH₂Cl₂(50 mL) and washed with satd NaHCO₃ (50 mL), brine (50 mL) and driedwith MgSO₄. The mixture was filtered, concentrated, and chromatographed(10:1 CH₂Cl₂:MeOH with 1% Et₃N) to give Example 144 (10 mg). MS m/z 647[C₃₃H₄₂N₈O₄S+H]⁺.

Example 145N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(2-hydroxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

Example 106 (250 mg, 0.36 mmol) and 50 mg of Pd/C (5%) were stirred in10 mL of MeOH under an H₂ atmosphere for 12 h. The mixture was filteredthrough a pad of celite, concentrated, and chromatogrpahed (10-100%EtOAc in hexanes) to give the Example 145 (15 mg). ESI MS m/z 610[C₃₀H₃₉N₇O₅S+H]⁺.

Example 1463-{4-[5-(2-Amino-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide

To a solution of 800 mg (1.03 mmol) of Example 109 in MeOH (40 mL) wasadded 3.6 g of NH₄CO₂ and 150 mg of Pd/C. The mixture was stirred atroom temperature for 3 h, filtered through celite, and concentrated. Theresulting residue was taken up in EtOAc (250 mL) and washed with asolution of water (10 mL) saturated NaHCO₃ (50 mL) and brine (20 mL).The organic layer was washed with brine (50 mL), dried over MgSO₄, andconcentrated to give the 655 mg of Example 146 (1.01 mmol). MS m/z 643[C₃₃H₃₈N₈O₄S+H]⁺.

Example 147N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[5-(2-dimethylamino-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide

Example 146 (250 mg, 0.389 mmol) was dissolved in 10 mL of MeOH.Formalin (0.6 mL of 37% aqueous formaldehyde) and 200 mg of Pd/C wereadded. The mixture was stirred under 1 atm H₂ for 48 h, filtered throughCelite, concentrated, and purified by chromatography (0 to 10% MeOH inCH₂Cl₂; 0.5% NH₄OH) to give Example 147 (120 mg). MS m/z 671[C₃₅H₄₂N₈O₄S+H]⁺.

Example 148N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-(2-morpholin-4-yl-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-benzamide

Example 146 (270 mg, 0.42 mmol) was dissolved in 8 mL of DMF followed by0.25 mL (2.1 mmol) of 2,6-lutidine and 600 mg (2.3 mmol) of1-bromo-2-(2-bromo-ethoxy)-ethane. The mixture was stirred at 80° C. for12 h, then was dissolved in EtOAc (300 mL) and washed with sat NaHCO₃,water, and brine. The organic portion was dried over MgSO₄, filtered,concentrated, and chromatographed (0 to 10% MeOH in CH₂Cl₂; 0.5% NH₄OH)to give Example 148 (52 mg). MS m/z 713 [C₃₇H₄₄N₈O₅S+H]⁺.

Example 149N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-benzamide

A solution of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-ethanone(829 mg; 2.97 mmol) and 3-amino-4-methyl benzoic acid methyl ester in 6mL of EtOH was stirred at 75° C., for 6 h. The mixture was cooled, andthe resulting precipitate was filtered and washed with cold EtOH toprovide 564 mg (1.55 mmol; 52%) of4-methyl-3-[2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-benzoicacid methyl ester as a white powder.

A suspension of 380 mg (1.05 mmol) of4-methyl-3-[2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-benzoicacid methyl ester and 203 mg (2.09 mmol) of KSCN in 4 mL of HOAc wasstirred at 100° C. for 4 h, when a precipitate formed. The mixture wascooled to room temperature, filtered, and washed with cold MeOH toprovide 283 mg of3-[2-mercapto-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (0.70 mmol; 67%). ESI MS m/z 405 [C₂₂H₂₀N₄O₂S+H]⁺.

To 1 mL of 20% HNO₃ was added 28 mg of HNO₂. This mixture was then addedto3-[2-mercapto-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (280 mg; 0.69 mmol) suspended in 5 mL of rapidlystirring HOAc over 15 min. After stirring an additional 5 min, thesolution was poured into ice-cold water. The pH was adjusted to about 7with NaHCO₃, and the mixture was extracted with EtOAc. The extract waswashed once with brine, dried with Na₂SO₄, filtered, and concentrated.The resulting residue was chromatographed (5-60% EtOAc in hexanes) toprovide 210 mg (0.56 mmol; 82%) of4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-benzoicacid methyl ester. ESI MS m/z 373 [C₂₂H₂₀N₄O₂+H]⁺.

To 119 mg (0.32 mmol) ofN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in 4 mL ofTHF at −78° C. was added slowly 0.42 mL of 1.6 M n-BuLi in hexanes (0.67mmol). The cold bath was removed, the mixture was stirred for 30 min.,and 0.34 mL of 1M LHMDS in THF (0.34 mmol) was added to the resultingpurple solution. THF was added as necessary to facilitate stirring andthe purple suspension was slowly transferred via syringe to a rapidlystirring solution of4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-benzoicacid methyl ester in 2 mL of THF at 0° C. After 20 min, cold MeOH wasadded, and the solution was partitioned between half saturated NH₄Cl andEtOAc. The EtOAc layer was then washed with brine. The washes wereextracted once with EtOAc, and the extracts were combined, dried withNa₂SO₄, filtered, and concentrated. Chromatography (0-3.5% (MeOH with 5%NH4OH) in CH₂Cl₂) provided Example 149. ESI MS m/z 613 [C₃₃H₃₆N₆O₄S+H]⁺.

Example 150N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide

Example 150 was prepared from2-tosyloxy-1-(5-methyl-1-isopropyl-1H-pyrazol-4-yl)-ethanone (Singh, S.P. et al, J. Indian Chem. Soc., 1997, 74, 940-942) in the same manner asExample 149. ESI MS m/z 579 [C₃₀H₃₈N₆O₄S+H]⁺.

Example 1513-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide

To a 0° C. solution of 7.55 (37.7 mmol) of5-ethyl-1-phenyl-1H-pyrazole-4-carbaldehyde (Example 86) in anhydrousTHF (100 mL) under N₂ was added over 5 minutes 15.7 (47.1 mmol) of 3.0 MMeMgBr in Et₂O. The mixture was warmed to room temperature and stirredfor 16 h, then 25 mL of 5% NH₄Cl was added and the mixture was extractedwith CH₂Cl₂ (70 mL), and the extract was washed with saturated NaCl (15mL). The organic layer separated, dried over MgSO₄, and concentrated togive 1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanol (7.91 g). ESI MS m/z217 [C₁₃H₁₆N₂O+H]⁺.

A solution of 7.9 g (36.5 mmol) of1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanol in 100 mL THF was stirredat rt over 24 g of activated MnO₂ for 23 h. The mixture was filteredthrough Celite and concentrated to give1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone (7.71 g). ESI MS m/z 215[C₁₃H₁₄N₂O⁺H]⁺.

To a solution of 5.40 g (25.3 mmol) of1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone in HOAc (30 mL) was addedHBr in HOAc (30 mL). Bromine (1.42 ml, 27.7 mmol) was added dropwise andthe mixture was stirred at rt for 45 minutes and was poured into icewater (500 mL). The liquid was decanted and remaining residue was washedwith water, then dissolved in CH₂Cl₂ (500 mL) and washed with satNaHCO₃, dried over MgSO₄, and concentrated to give 7.20 g of2-bromo-1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone.

A solution of 7.20 g (24.6 mmol) of2-bromo-1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone and 8.52 g (51.6mmol) of 3-amino-4-methyl benzoic acid methyl ester in EtOH (30 mL) washeated to 75° C. for 16 h. The solution was cooled and allowed to standat rt for 6 h. The solids were filtered off and washed with cold EtOH toprovide3-[2-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-4-methyl-benzoicacid methyl ester as a white powder (3.75 g). ESI MS m/z 378[C₂₂H₂₃N₃O₃+H]⁺.

A suspension of 3.75 g (9.94 mmol) of3-[2-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-4-methyl-benzoicacid methyl ester and 2.9 g (30 mmol) of KSCN in 25 mL of HOAc wasstirred at 100° C. for 4 h. The mixture was allowed to cool overnightbefore being filtered and washed with cold MeOH. The solids were driedto provide 2.65 g of3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-mercapto-imidazol-1-yl]-4-methyl-benzoicacid methyl ester as an off-white solid. ESI MS m/z 419[C₂₃H₂₂N₄O₂S+H]⁺.

The above thioimidazole (2.65 g, 6.33 mmol) was suspended in 5 mL ofHOAc and 0.63 mL of water and heated to 35° C. Hydrogen peroxide (2.36g, 20.8 mmol) was added over 15 minutes. After heating at 40° C. for 35minutes, the mixture was cooled to 25° C. and quenched with 10% Na₂SO₃(1 mL). After 15 min, concentrated NH₄OH (20 mL) added and the resultinggummy orange solid was washed with water, then dissolved in EtOAc andwashed with brine, dried over MgSO₄,concentrated, and chromatographed(10 to 80% EtOAc in hexanes). The desired fractions were stirred in DCMwith PS-TBD resin and decolorizing charcoal, filtered through Celite,and concentrated to give 1.85 g of3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester. ESI MS m/z 387 [C₂₃H₂₂N₄O₂+H]⁺.

To a solution of 70 mg (0.25 mmol) ofN-[3-amino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-methanesulfonamidein 5 mL of THF under N₂ was added 1.04 mL of LHMDS (1.0 M). The mixturewas stirred at rt for 15 minutes when a solution of3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (100 mg, 0.026 mmol) in 5 mL of THF (5 mL) was added.After stirring for 45 minutes, 10 mL of saturated NaHCO₃ was added. Themixture was extracted with CH₂Cl₂ (100 ml), dried with Na₂SO₄, filtered,concentrated, and chromatographed (30 to 100% EtOAc in hexanes) to giveExample 151 (69 mg). ESI MS m/z 625 [C₃₄H₃₆N₆O₄S+H]⁺.

Example 152N-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide

Example 152 was prepared from 5-tert-butyl-2-methyl-pyridin-3-ylamine(see U.S. provisional application 60/567,693) and3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (Example 151) in the same manner as Example 151. ESIMS m/z 519 [C₃₂H₃₄N₆O+H]⁺.

Example 153N-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide

Example 153 was prepared from 5-tert-butyl-2-methoxy-phenylamine and3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (Example 151) in the same manner as Example 151. ESIMS m/z 534 [C₃₃H₃₅N₅O₂+H]⁺.

Example 1543-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-(2-methoxy-5-trifluoromethyl-phenyl)-4-methyl-benzamide

Example 154 was prepared from 2-methoxy-5-trifluoromethyl-phenylamineand3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (Example 151) in the same manner as Example 151. ESIMS m/z 546 [C₃₀H₂₆F₃N₅O₂+H]⁺.

Example 155N-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide

Example 155 was prepared from3-amino-5-tert-butyl-2-methoxy-benzonitrile and3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (Example 151) in the same manner as Example 151. ESIMS m/z 559 [C₃₄H₃₄N₆O₂+H]⁺.

Example 156N-(5-tert-Butyl-2-methanesulfinyl-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide

Example 156 was prepared from 5-tert-butyl-2-methanesulfinyl-phenylamineand3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (Example 151) in the same manner as Example 151. ESIMS m/z 566 [C₃₃H₃₅N₅O₂S+H]⁺.

Example 157N-(5-tert-Butyl-3-methanesulfonylamino-2-methyl-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide

Example 157 was prepared fromN-(3-amino-5-tert-butyl-2-methyl-phenyl)-methanesulfonamide and3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (Example 151) in the same manner as Example 151. ESIMS m/z 611 [C₃₄H₃₈N₆O₃S+H]⁺.

Example 158N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide

Example 158 was prepared fromN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide and3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (Example 151) in the same manner as Example 151. ESIMS m/z 627 [C₃₄H₃₈N₆O₄S+H]⁺.

Example 1593-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-4-methyl-benzamide

Example 159 was prepared fromN-(3-amino-2-methoxy-5-trifluoromethyl-phenyl)-methanesulfonamide and3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoicacid methyl ester (Example 151) in the same manner as Example 151. ESIMS m/z 639 [C₃₁H₂₉F₃N₆O₄S+H]⁺.

Example 160N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl-imidazol-1-yl)-benzamide

To a solution of 2-bromo-1-pyridin-3-yl-ethanone hydrobromide (Barlin,G. B. et al. Australian J. Chem, 1989, 1735) (500 mg, 1.78 mmol) in 2 mlof EtOH was added 3-amino-4-methyl-benzoic acid methyl ester (Lancaster;294 mg, 1.78 mmol) and NaHCO₃ (750 mg, 8.9 mmol), and the mixture wasstirred for 2 h. The mixture was then filtered and washded with MeOH,then the filtrated was concentrated to a small volume and dissolved inEtOAc. The EtOAc slurry was washed with water and brine, and the washeswere extracted once more with EtOAc. The combined organic portions weredried with Na₂SO₄, filtered, concentrated, and chromatographed (0-5%MeOH in dichloromethane) to provide 84.5 mg of4-methyl-3-(2-oxo-2-pyridin-3-yl-ethylamino)-benzoic acid methyl ester.

A mixture of 4-methyl-3-(2-oxo-2-pyridin-3-yl-ethylamino)-benzoic acidmethyl ester (84.5 mg; 0.297 mmol) and KSCN (58 mg; 0.59 mmol) in 1.5 mLof HOAc were heated to 100° C. for 2 h. The mixture was then poured intowater and carefully brought to pH 8 with NaOH. The mixture wasimmediately extracted with EtOAc, and the extract washed with brine. Thewashes were extracted once more with EtOAc, and the combined extractswere dried with Na₂SO₄, filtered, and concentrated to provide3-(2-mercapto-4-pyridin-3-yl-imidazol-1-yl)-4-methyl-benzoic acid methylester (90 mg; 0.28 mmol; 93%). ESI MS m/z 326 [C₁₇H₁₅N₃O₂S+H]⁺.

To a suspension of 85 mg (0.261 mmol) of3-(2-mercapto-4-pyridin-3-yl-imidazol-1-yl)-4-methyl-benzoic acid methylester in 1.8 mL of water was added 0.68 mL of concentrated HNO₃ and 2 mgof NaNO₂. After 2 h, the mixture was cooled to 0° C. and 4N NaOH wasadded until the pH reached about 10. The mixture was stirred for 30 minthen HOAc was added until the pH reached about 6. The resultingprecipitate was filtered, washed with water and dried to provide 16 mg(0.057 mmol; 22%) of 4-methyl-3-(4-pyridin-3-yl-imidazol-1-yl)-benzoicacid.

4-Methyl-3-(4-pyridin-3-yl-imidazol-1-yl)-benzoic acid (15 mg; 0.054mmol), N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (29mg; 0.11), and HATU (49 mg; 0.11 mmol) were dissolved in 1 mL of DMF,and the mixture was chilled to 0° C. Diisopropylethylamine (19 μL; 0.11mmol) was then added, the cold-bath was removed, and the mixture wasstirred overnight. The mixture was then poured into water and extractedwith EtOAc. The organic portion was washed with NaHCO₃ and brine, andthe washes were extracted once with EtOAc. The extracts were combined,dried with Na₂SO₄, filtered, and concentrated. Chromatography (0-6.5%MeOH/0.5% NH₄OH in CH₂Cl₂) provided 23 mg (0.043 mmol; 80%) of Example160. ESI MS m/z 534 [C₂₈H₃₁N₅O₄S+H]⁺.

Example 161N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[6-(2-morpholin-4-yl-ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}-benzamide

Example 1 (500 mg, 0.88 mmol), Ph₃As (27 mg, 0.088 mmol), and CsF (295mg, 1.93 mmol) were combined in NMP (2.5 mL) and degassed by thefreeze-pump-thaw method. 2,6-Di-tert-butyl-4-methylphenol (fewcrystals), Pd₂(dba)₃ (20 mg, 0.022 mmol), and tributyl vinyl tin (310μL, 1.06 mmol) were added and the reaction was heated at 70° C.overnight. Additional Ph₃As (27 mg, 0.088 mmol) and Pd₂(dba)₃ (20 mg,0.022 mmol) were added and the reaction heated at 70° C. overnight.Water and EtOAc were added and the layers were separated. The organiclayer was dried over sodium sulfate, filtered, and evaporated. Theproduct,N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-vinyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide,was used without purification for the next step. ESI MS m/z 561[C₂₉H₃₂N₆O₄S+H]⁺.

The above impure vinylpyridine (300 mg) was dissolved in EtOH (5 mL).Morpholine (120 microL) and HOAc (3 drops) were added and the mixturewas heated in a sealed tube at 50° C. overnight. The reaction wasevaporated and chromatographed (3% ammonium hydroxide, 10% MeOH, 20%chloroform, 67% EtOAc) and the product containing fractions evaporated.The residue was further purified by semi-prep HPLC to provide Example161 (21 mg). ESI MS m/z 648 [C₃₃H₄₁N₇O₅S+H]⁺.

Example 162N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[6-(2-methylamino-ethyl)-pyridin-3-yl]-[1,2,3]triazol-1-yl}-benzamide

Example 162 was prepared fromN-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-vinyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide(Example 151) and methylamine in the same manner as Example 151. ESI MSm/z 592 [C₃₀H₃₇N₇O₄S+H]⁺.

Example 163N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino-ethyl)-pyridin-3-yl]-[1,2,3]triazol-1-yl}-4-methyl-benzamide

Example 163 was prepared fromN-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-vinyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide(Example 151) and dimethylamine in the same manner as Example 151. ESIMS m/z 606 [C₃₁H₃₉N₇O₄S+H]⁺.

Methods of Use

In accordance with the invention, there are provided novel methods ofusing the compounds of the formula (I). The compounds disclosed thereineffectively block inflammatory cytokine production from cells. Theinhibition of cytokine production is an attractive means for preventingand treating a variety of cytokine mediated diseases or conditionsassociated with excess cytokine production, e.g., diseases andpathological conditions involving inflammation. Thus, the compounds areuseful for the treatment of diseases and conditions as described in theBackground section, including the following conditions and diseases:

osteoarthritis, atherosclerosis, contact dermatitis, bone resorptiondiseases, reperfusion injury, asthma, multiple sclerosis, Guillain-Barresyndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versushost disease, systemic lupus erythematosus and insulin-dependentdiabetes mellitus, rheumatoid arthritis, toxic shock syndrome,Alzheimer's disease, diabetes, inflammatory bowel diseases, acute andchronic pain as well as symptoms of inflammation and cardiovasculardisease, stroke, myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, syndromes associated withhemodialysis, leukopherisis, granulocyte transfusion associatedsyndromes, and necrotizing entrerocolitis, complications includingrestenosis following percutaneous transluminal coronary angioplasty,traumatic arthritis, sepsis, chronic obstructive pulmonary disease andcongestive heart failure. The compounds of the invention may also beuseful for anticoagulant or fibrinolytic therapy (and the diseases orconditions related to such therapy) as described in the provisionalapplication No. 60/403,422.

The compounds of the invention are also p38 MAP kinase inhibitors.Activity can be demonstrated by using methods known in the art. See forexample Branger et al., (2002) J Immunol. 168: 4070-4077. As disclosedin the Background of the Invention, the compounds of the invention willtherefore be useful for treating, in addition to inflammatory diseases,oncological diseases. These diseases include but are not limited tosolid tumors, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid and their distant metastases. Thosedisorders also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma and mesothelioma.

Examples of brain cancers include, but are not limited to brain stem,optic and hypophtalmic glioma, cerebella and cerebral astrocytoma,medulloblastoma, ependymoma, as well as pituitary, neuroectodermal andpineal tumor.

Examples of peripheral nervous system tumors include, but are notlimited to neuroblastoma, ganglioneuroblastoma, and peripheral nervesheath tumors.

Examples of tumors of the endocrine and exocrine system include, but arenot limited to thyroid carcinoma, adrenocortical carcinoma,pheochromocytoma, and carcinoid tumors.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer.

Tumors of the female reproductive organs include, but are not limited toendometrial, cervical, ovarian, vaginal, and vulvar cancer, as well assarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallblader, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),hepatoblastoma, cholangiocarcinoma (intrahepatic bile duct carcinoma),and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, Hodgkins lymphoma, cutaneous T-cell lymphoma,and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, Ewings sarcoma, malignant fibrous histiocytoma,lymphosarcoma, angiosarcoma, and rhabdomyosarcoma. Leukemias include,but are not limited to acute myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia,and hairy cell leukemia.

Plasma cell dyscrasias include, but are not limited to multiple myeloma,and Waldenstrom's macroglobulinemia.

These disorders have been well characterized in man, but also exist witha similar etiology in other mammals, and can be treated bypharmaceutical compositions of the present invention.

For therapeutic use, the compounds may be administered in anyconventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

The compounds may be administered alone or in combination with adjuvantsthat enhance stability of the inhibitors, facilitate administration ofpharmaceutic compositions containing them in certain embodiments,provide increased dissolution or dispersion, increase inhibitoryactivity, provide adjunct therapy, and the like, including other activeingredients. Advantageously, such combination therapies utilize lowerdosages of the conventional therapeutics, thus avoiding possibletoxicity and adverse side effects incurred when those agents are used asmonotherapies. The above described compounds may be physically combinedwith the conventional therapeutics or other adjuvants into a singlepharmaceutical composition. Reference is this regard may be made toCappola et al.: U.S. patent application Ser. No. 09/902,822, PCT/US01/21860 and U.S. application Ser. No. 10/214,782, each incorporated byreference herein in their entirety. Advantageously, the compounds maythen be administered together in a single dosage form. In someembodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 5%, but more preferablyat least about 20%, of a compound of formula (I) (w/w) or a combinationthereof. The optimum percentage (w/w) of a compound of the invention mayvary and is within the purview of those skilled in the art.Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

As mentioned above, dosage forms of the compounds described hereininclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 1-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. Referencein this regard may also be made to U.S. provisional application No.60/339,249. As the skilled artisan will appreciate, lower or higherdoses may be required depending on particular factors. For instance,specific dosage and treatment regimens will depend on factors such asthe patient's general health profile, the severity and course of thepatient's disorder or disposition thereto, and the judgment of thetreating physician.

Biological Assays

Inhibition of TNF Production in THP Cells

The inhibition of cytokine production can be observed by measuringinhibition of TNFα in lipopolysaccharide stimulated THP cells (forexample, see W. Prichett et al., 1995, J. Inflammation, 45, 97). Allcells and reagents were diluted in RPMI 1640 with phenol red andL-glutamine, supplemented with additional L-glutamine (total: 4 mM),penicillin and streptomycin (50 units/ml each) and fetal bovine serum(FBS, 3%) (GIBCO, all conc. final). Assay was performed under sterileconditions; only test compound preparation was nonsterile. Initial stocksolutions were made in DMSO followed by dilution into RPMI 1640 2-foldhigher than the desired final assay concentration. Confluent THP.1 cells(2×10⁶ cells/ml, final conc.; American Type Culture Company, Rockville,Md.) were added to 96 well polypropylene round bottomed culture plates(Costar 3790; sterile) containing 125 μl test compound (2 foldconcentrated) or DMSO vehicle (controls, blanks). DMSO concentration didnot exceed 0.2% final. Cell mixture was allowed to preincubate for 30min, 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS; 1μg/ml final; Siga L-2630, from E. coli serotype 0111.B4; stored as 1mg/ml stock in endotoxin screened distilled H₂O at −80° C.). Blanks(unstimulated) received H₂O vehicle; final incubation volume was 250 μl.Overnight incubation (18-24 hr) proceeded as described above. Assay wasterminated by centrifuging plates 5 min, room temperature, 1600 rpm(400×g); supernatants were transferred to clean 96 well plates andstored −80° C. until analyzed for human TNFα by a commercially availableELISA kit (Biosource #KHC3015, Camarillo, Calif.). Data was analyzed bynon-linear regression (Hill equation) to generate a dose response curveusing SAS Software System (SAS institute, Inc., Cary, N.C.).

The calculated IC₅₀ value is the concentration of the test compound thatcaused a 50% decrease in the maximal TNFα production.

Preferred compounds have an IC₅₀<1 uM in this assay.

Inhibition of Other Cytokines

By similar methods using peripheral blood monocytic cells, appropriatestimuli, and commercially available ELISA kits (or other method ofdetection such as radioimmunoassay), for a particular cytokine,inhibition of IL-1beta, GM-CSF, IL-6 and IL-8 can be demonstrated forpreferred compounds (for example, see J. C. Lee et al., 1988, Int. J.Immunopharmacol., 10, 835).

All references disclosed in this application including patents, patentpublications and literature citations are incorporated herein byreference in their entirety.

1. A compound of the formula (I)

wherein: Ar¹ is chosen from (i), (ii) and (iii) below: (i) a carbocyclesubstituted by R¹, R² and R^(x),

wherein one of E or F is nitrogen and the other is carbon, R¹ iscovalently attached to either E or F, and when nitrogen is N—R¹ thedouble bond between E and F is not present;

wherein c is a benzo ring fused to ring d which is a 5-7 memberedheterocyclic ring optionally substituted by an oxo (═O) group and one totwo R groups each independently being H or C1-3 alkyl; R¹ is chosen fromhydrogen, NO₂, —N(R^(c))₂, J-C(O)—N(R^(c))—, J-S(O)_(m)—N(R^(c))—, C1-6alkylS(O)_(m)—, or R¹ is chosen from C1-6 alkyl, C3-7 cylcoalkyl, C1-5alkoxyl or C3-7 cycloalkoxyl, C1-5 alkylthiol or C3-7 cycloalkylthiol,C1-5 acyl, C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, C2-5alkenyl, C2-5 alkynyl, heterocycle, heterocycleC1-6 alkyl, heteroaryl,heteroarylC1-6 alkyl and nitrile; each of the aforementioned wherepossible are optionally partially or fully halogenated or are optionallyfurther substituted with alkylsulfonylamino, aminocarboxyl, alkoxyl,amino, alkylamino, dialkylamino, hydroxyl, oxo, nitro or nitrile; R² ischosen from: hydrogen, halogen, nitrile, C1-5 alkylS(O)_(m)—,arylS(O)_(m), J-O—C(O)—O—, N(R^(c))₂—C(O)—(CH₂)_(n)—, C1-6 acetyl,aroyl, C1-6alkoxycarbonyl, C1-6 alkyl, C3-7cycloalkyl, C1-6 alkoxy,C3-5cycloalkoxy, C1-5 alkylC1-5 alkoxy, hydroxy, hydroxy C1-5 alkyl, andamino optionally mono- or di-substituted by C1-5 alkyl, aryl or arylC1-5 alkyl; each of the aforementioned where possible are optionallypartially or fully halogenated or are optionally further substitutedwith C1-3 alkyl, alkylsulfonylamino, alkoxyl, amino, alkylamino,dialkylamino, hydroxyl, oxo, nitro or nitrile; each R^(x) is chosen fromC1-6 alkyl or C3-7 cycloalkyl each being optionally substituted by C1-3alkyl and optionally partially or fully halogenated, C1-4 acyl, aroyl,C1-4 alkoxy, C1-5alkylS(O)_(m)—, each may optionally be partially orfully halogenated, halogen, C1-6 alkoxycarbonyl, carbocyclesulfonyl;each R^(c) is independently hydrogen or C1-5 alkyl; D, A and B in

of the formula (I) are each independently chosen from N or CH whereinthe hydrogen atom is optionally replaced by R⁶; Het is a heterocyclic orheteroaryl ring wherein Het is optionally substituted by one to threeR⁵; m is 0,1 or 2; J is chosen from C1-10 alkyl and C3-7cycloalkyl eachoptionally substituted by R^(b); R³, R⁴, R⁶, R⁷ and R⁸ are eachindependently chosen from hydrogen, halogen, C1-5 alkyl, C1-5 alkoxy,C1-5 alkylC1-5 alkoxy, hydroxy, hydroxy C1-5 alkyl or amino optionallymono- or di-substituted by C1-5 alkyl, aryl or aryl C1-5 alkyl; R⁵ is:R^(a), —O—R^(a), —S(O)_(m)—R^(a), —N(R^(a))₂, —C(O)—R^(a),—NH(CR⁷R⁸)_(n)—R^(a), N(R^(a))₂—(CH₂)₁₋₂— —(CR⁷R⁸)_(n)—R^(a),—O(CR⁷R⁸)_(n)—R^(a), —C(O)—O(CR⁷R⁸)_(n)—R^(a), —C(O)(CR⁷R⁸)_(n)—R^(a)—C(O)C(O)R^(a), —C(O)C(O)OR^(a), —C(O)NHR^(a), or —C(O)NH(CR⁷R⁸)_(n)—,each optionally substituted by C1-3 alkyl, halogen or hydroxy, wherein nis 1-5; or R⁵ is aryl, heteroaryl or heterocyclyl each optionallysubstituted by R^(a); R^(a) and R^(b) are each independently chosen fromhydrogen, C1-6 alkyl, hydroxyC1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl,carbocycle, carbocycleC0-2 alkyl, aryl, heterocycle, heteroaryl, C1-5alkoxy, C1-5 alkylthio, amino, C1-5 alkylamino, C1-5 dialkylamino,arylamino, aryl C1-5 alkylamino, diarylamino, C1-5 acyl, C1-5alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, each of the aforementionedare optionally partially or fully halogenated, or R^(a) and R^(b) arechosen from C1-5 alkylsulphonylamino, hydroxy, oxo, halogen, —CF₃,—CH₂—CF₃, nitro and nitrile, wherein each carbocycle, heterocycle orheteroaryl for R^(a) and R^(b) is optionally substituted by amino, C1-3alkyl, halogen or hydroxy; and X is O or S or the pharmaceuticallyacceptable salts thereof.
 2. The compound according to claim 1 wherein

of the formula (I) is chosen from:

Het is

J is chosen from C1-10 alkyl, aryl and C3-7 cycloalkyl each optionallysubstituted by R^(b); R² is independently chosen from hydrogen,J-O—C(O)—O—, C1-6 alkoxy, C1-6 alkyl, C1-6 acetyl, aroyl, halogen,methoxycarbonyl, phenylsulfonyl, C1-5 alkylS(O)_(m)— and C3-7 cycloalkyloptionally substituted by C1-3 alkyl, each R² where possible may beoptionally partially or fully halogenated; R¹ is chosen from H, C1-6alkyl, C1-5 alkylS(O)_(m)—, J-S(O)_(m)—N(R^(c))—, C1-5 alkoxyl, C1-5alkylthiol , NH₂—C(O)—(CH₂)_(n)—, (R^(c))₂N C1-6 alkyl, C1-5acylNH—,—NH₂, —NO₂, heteroaryl chosen from pyrazole, triazole, imidazole andtetrazole, and nitrile; ring d is a 5-6 membered heterocyclic ring suchthat rings c and d fuse to form the following:

where each R is independently H or C1-3 alkyl; R³ and R⁴ are eachindependently chosen from hydrogen, C1-3 alkoxy, C1-3 alkyl and halogen;n is 1-4; R^(a) and R^(b) are each independently chosen from hydrogen,C1-6 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkylC0-2 alkyl, aryl,C1-5 alkoxy, C1-5 alkylthio, amino, C1-5 alkylamino, C1-5 dialkylamino,arylamino, C1-5 acyl, C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino,aryl C1-5alkylamino, C1-5 alkylsulphonylamino, hydroxy, halogen, —CF₃,—CH₂—CF₃ nitro, nitrile, or R^(a) and R^(b) are chosen from; heterocyclechosen from pyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxalanyl,piperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone,1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl, aziridinyl,pentamethylene sulfide, pentamethylene sulfoxide, pentamethylenesulfone, tetramethylene sulfide, tetramethylene sulfoxide andtetramethylene sulfone and heteroaryl chosen from thienyl, furanyl,isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl,pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl,indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl; wherein each aryl,heterocycle or heteroaryl for R^(a) and R^(b) is optionally substitutedby amino, C1-3 alkyl, halogen or hydroxy; and X is O.
 3. The compoundaccording to claim 2 and wherein Ar¹ is chosen from (i) and (ii); R⁵ is:a) R^(a), —O—R^(a), —S(O)_(m)—R^(a), —N(R^(a))₂, N(R^(a))₂—(CH₂)₁₋₂—,—NH(CR⁷R⁸)_(n)—R^(a), —(CR⁷R⁸)_(n)—R^(a) or —O(CR⁷R⁸)_(n)—R^(a); or R⁵is: b) —C(O)—R^(a), —C(O)—O(CR⁷R⁸)_(n)—R^(a), —C(O)(CR⁷R⁸)_(n)—R^(a),—C(O)NHR^(a), —C(O)NH(CR⁷R⁸)_(n)—, —C(O)C(O)R^(a) or —C(O)C(O)OR^(a);each of the above R⁵ is optionally substituted by C1-3 alkyl, halogen orhydroxyl, and wherein n is 1-3
 4. The compound according to claim 3wherein Ar¹ is:

or Ar¹ is cyclobutyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl orindenyl each substituted with one R¹, one R^(x), and one R² group; R¹ isnitrile, NO₂, NH₂, C1-3acylNH—, J-S(O)_(m)—N(R^(c))— where J is C1-10alkyl, or R¹ is

R² is independently chosen from C1-6 alkyl, C1-6 alkylS(O)_(m)—, C1-3alkoxy and C3-6 cycloalkyl optionally substituted by C1-3 alkyl , eachmay optionally be partially or fully halogenated; R³ and R⁴ are eachindependently chosen from hydrogen, C1-3 alkyl, fluoro and chloro; R⁶ ischosen from hydrogen and amino; n is 1-2; R^(a) and R^(b) are eachindependently chosen from hydrogen, C1-6 alkyl, C3-7 cycloalkylC0-2alkyl, aryl, C1-5 alkoxy, amino, C1-5 alkylamino, C1-5 dialkylamino,arylamino, aryl C1-5alkylamino, C1-3 acyl, C1-5 alkoxycarbonyl, C1-5acyloxy, C1-5 acylamino, C1-5 sulphonylamino, hydroxy, halogen, —CF₃,—CH₂—CF₃ nitro, nitrile; or R^(a) is chosen from pyrrolidinyl,pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,thiomorpholinyl sulfone, piperidinyl, piperazinyl, homopiperazinyl,piperidinonyl, tetrahydropyrimidonyl, aziridinyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein each aryl,heterocycle or heteroaryl for R^(a) and R^(b) is optionally substitutedby amino, C1-3 alkyl, halogen or hydroxy.
 5. The compound according toclaim 4 and wherein Ar¹ is

R¹ is: J-S(O)₂—NH—, where J is C1-5 alkyl, or R¹ is nitrile, NO₂, NH₂ orC1-3acylNH—; wherein R^(x)═R² each are independently chosen from C1-5alkyl, C1-5 alkylS(O)_(m)—, C1-4 alkoxy and and C3-5 cycloalkyloptionally substituted by C1-2 alkyl, each may optionally be partiallyor fully halogenated; R⁸ is hydrogen, methyl, ethyl, CH₂OH and CH₂OCH₃.6. The compound according to claim 5 and wherein R^(a) is chosen fromhydrogen, C1-6 alkyl, C3-6 cycloalkylC0-2 alkyl, phenyl, C1-5 alkoxy,amino, C1-5 alkylamino, C1-5 dialkylamino, arylamino, arylC1-5alkylamino, C1-3 acyl, C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5acylamino, hydroxy, halogen, —CF₃, —CH₂—CF₃; or R^(a) is chosen frommorpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinylsulfone, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl,piperidinonyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl whereineach phenyl, heterocycle or heteroaryl for R^(a) is optionallysubstituted by amino, C1-3 alkyl, halogen or hydroxy.
 7. The compoundaccording to claim 6 and wherein R^(a) is chosen from hydrogen, C1-6alkyl, C3-6 cycloalkyl, phenyl, C1-5 alkoxy, C1-5 alkoxycarbonyl, amino,C1-5 alkylamino, C1-5 dialkylamino, arylamino, aryl C1-5alkylamino, C1-5acyloxy, C1-5 acylamino, hydroxy, halogen, —CF₃, —CH₂—CF₃; or R^(a) ischosen morpholinyl, piperidinyl piperazinyl, homopiperazinyl,pyrrolidinyl and pyridinyl wherein each phenyl, heterocycle orheteroaryl for R^(a) is optionally substituted by amino, C1-3 alkyl,halogen or hydroxy.
 8. The compound according to claim 7 and wherein

of the formula (I) is chosen from:

Het is;

Ar¹ is

R⁵ is: C1-5 alkyl, C3-6 cycloalkyl, N(R^(a))₂(CH₂)₁₋₂—, halogen, C1-3alkoxy, hydroxy, —N(R^(a))₂, —CF₃, —CH₂—CF₃, aryl, —S(O)_(m)—R^(a),—NH(CR⁷R⁸)_(n)—R^(a) or —(CR⁷R⁸)_(n)—N(R^(a))₂ each optionallysubstituted by C1-3 alkyl, halogen or hydroxy, or R⁵ is —C(O)R^(a),—C(O)C(O)R^(a), —C(O)NHR^(a); R^(a) is chosen from hydrogen,morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyridinyl, C₁₋₅mono or dialkylamino, arylamino, C3-6cylcoalkyl, C1-5 alkyl and C1-3alkoxy wherein each phenyl or heterocycle for R^(a) is optionallysubstituted by amino, C1-3 alkyl, halogen or hydroxyl.
 9. The compoundaccording to any of claims 1-8 and wherein


10. A compound chosen from[2-(4-{1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-1,2,3-triazol-4-yl}-2-phenyl-2H-pyrazol-3-yl)-ethyl]-carbamicacid benzyl ester3-[4-(1-Benzyl-2-ethyl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(1-Cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(2-Acetyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(2-Benzenesulfonyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(2-Benzoyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(2-Benzoyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(2-Benzyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(2-Benzyloxymethyl-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(2-Cyclobutyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(2-Cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(2-Cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[5-(2-hydroxy-1,1-dimethyl-ethyl)-3-methanesulfonylamino-2-methoxy-phenyl]-4-methyl-benzamide3-[4-(2-Isopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(2-tert-Butyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(3-Benzyl-2-ethyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(3-tert-Butyl-2-cyclopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(3-tert-Butyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(3-tert-Butyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(3-tert-Butyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-(2-methoxy-5-trifluoromethyl-phenyl)-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(6-Amino-pyridin-3-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-{4-[1-(1-Benzyl-piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-{4-[2-(1-Benzyloxy-cyclopropyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-{4-[2-(2-Benzyloxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-{4-[2-(4-Benzyl-piperazin-1-yl)-1-methyl-1H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-{4-[2-(4-Benzyl-piperazin-1-yl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-{4-[2-(Hydroxy-phenyl-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-{4-[5-(2-Amino-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide4-(4-{1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-1,2,3-triazol-4-yl}-2-cyclopropyl-2H-pyrazol-3-yl)-piperidine-1-carboxylicacid tert-butyl esterN-(5-tert-Butyl-2-methanesulfinyl-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-2-methanesulfinyl-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-2-methanesulfinyl-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-(4-furan-3-yl-1,2,3-triazol-1-yl)-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3,4-dimethyl-5-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-piperidin-4-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-dimethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,2-diethyl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-diisopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-ethyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-isopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-isopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-dimethylamino-1-methyl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfonyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfinyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butylsulfanyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-hydroxymethyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-formyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclobutyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-dimethylamino-3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2,3-diethyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2,3-dihydro-imidazo[2,1-b]thiazol-5-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-cyclopropyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-cyclopropyl-2-isopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-tert-butyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-ethyl-2-phenyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-cyclopropyl-1-isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-dimethylamino-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-cyclopropylamino-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(4-fluoro-phenyl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(1-tert-butyl-piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-cyclopropyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(hydroxy-phenyl-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(2,2-dimethyl-propionyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-2,2-dimethyl-propyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-1-methyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(2-hydroxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-cyclopropyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(cyclopropyl-hydroxy-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[5-(2-dimethylamino-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino-ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino-ethylamino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-5-methoxy-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-fluoro-4-methyl-5-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-chloro-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-fluoro-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-methyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-methyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl-imidazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-methylamino-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-thiazol-5-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyrimidin-5-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-trifluoromethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(tetrahydro-furan-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(4-methyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-phenylsulfanyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-methyl-1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[2-methyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-morpholin-4-yl-thiazol-5-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[6-(2-methylamino-ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[6-(2-morpholin-4-yl-ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-pyridin-4-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-piperidin-4-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-4-yl-[1,2,3]triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-phenyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-(2-morpholin-4-yl-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(1-methyl-2-piperazin-1-yl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-piperazin-1-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-cyclohexane)]-[1,2,3]triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-morpholin-4-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-(2′-methyl-cycloproane))]-[1,2,3]triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-methylsulfanyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(2-methyl-propane-2-sulfonyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methyl-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methyl-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(5-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideandN-[5-(2-Hydroxy-1,1-dimethyl-ethyl)-3-methanesulfonylamino-2-methoxy-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideor the pharmaceutically acceptable salts thereof.
 11. The compoundaccording to claim 10 wherein the compound is chosen from3-[4-(6-Amino-pyridin-3-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideN-(5-tert-Butyl-2-methanesulfinyl-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3,4-dimethyl-5-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-dimethylamino-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(6-cyclopropylamino-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino-ethylamino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-5-methoxy-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino-ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-fluoro-4-methyl-5-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-chloro-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-fluoro-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-methyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-methyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-methylamino-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyrimidin-5-yl-1,2,3-triazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-trifluoromethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(4-methyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[6-(2-methylamino-ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[6-(2-morpholin-4-yl-ethyl)-pyridin-3-yl]-1,2,3-triazol-1-yl}-benzamideandN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(5-methoxy-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide.12. The compound according to claim 10 wherein the compound is chosenfrom:3-[4-(2-Benzoyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(2-Benzoyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(2-Cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(2-Cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[5-(2-hydroxy-1,1-dimethyl-ethyl)-3-methanesulfonylamino-2-methoxy-phenyl]-4-methyl-benzamide3-[4-(2-Isopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(2-tert-Butyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(3-Benzyl-2-ethyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(3-Ethyl-2-phenyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(3-tert-Butyl-2-cyclopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(3-tert-Butyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(3-tert-Butyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(3-tert-Butyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-{4-[2-(2-Benzyloxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-{4-[2-(4-Benzyl-piperazin-1-yl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-{4-[2-(Hydroxy-phenyl-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-diisopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-isopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-isopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfonyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfinyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2,3-diethyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-cyclopropyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-cyclopropyl-2-isopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-tert-butyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-ethyl-2-phenyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-cyclopropyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(hydroxy-phenyl-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(2,2-dimethyl-propionyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-2,2-dimethyl-propyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-1-methyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(2-hydroxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-phenylsulfanyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[2-methyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-pyridin-4-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-phenyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-piperazin-1-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-cyclohexane)]-[1,2,3]triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-morpholin-4-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-(2′-methyl-cycloproane))]-[1,2,3]triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-methylsulfanyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butylsulfanyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(2-methyl-propane-2-sulfonyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamide3-{4-[2-(1-Benzyloxy-cyclopropyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-cyclopropyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide3-[4-(2-Benzyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-1-phenyl-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-hydroxymethyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-2-methanesulfinyl-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methyl-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-[5-(2-Hydroxy-1,1-dimethyl-ethyl)-3-methanesulfonylamino-2-methoxy-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(cyclopropyl-hydroxy-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamide3-[4-(2-Acetyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-formyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideandN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2,3-dihydro-imidazo[2,1-b]thiazol-5-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamide.13. The compound according to claim 10 wherein the compound is chosenfrom:[2-(4-{1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-1,2,3-triazol-4-yl}-2-phenyl-2H-pyrazol-3-yl)-ethyl]-carbamicacid benzyl ester3-[4-(1-Cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-{4-[1-(1-Benzyl-piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-{4-[5-(2-Amino-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide4-(4-{1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-1,2,3-triazol-4-yl}-2-cyclopropyl-2H-pyrazol-3-yl)-piperidine-1-carboxylicacid tert-butyl esterN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-piperidin-4-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-dimethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-cyclopropyl-1-isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(4-fluoro-phenyl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(1-tert-butyl-piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[5-(2-dimethylamino-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-methyl-1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-piperidin-4-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-(2-morpholin-4-yl-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideandN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamide.14. The compound according to claim 10 wherein the compound is chosenfrom:N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-thiazol-5-yl-1,2,3-triazol-1-yl)-benzamideandN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-morpholin-4-yl-thiazol-5-yl)-1,2,3-triazol-1-yl]-benzamide.15. The compound according to claim 10 wherein the compound is chosenfrom:3-[4-(2-Benzyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(2-tert-Butyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(3-Ethyl-2-phenyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(3-tert-Butyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(3-tert-Butyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-{4-[2-(Hydroxy-phenyl-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-diisopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-isopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-cyclopropyl-3-isopropyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfonyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-methanesulfinyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-tert-butylsulfanyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-hydroxymethyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(2,3-diethyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(3-ethyl-2-phenyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(hydroxy-phenyl-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-2,2-dimethyl-propyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-1-methyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(2-hydroxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-cyclopropyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(1-hydroxy-ethyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[2-(cyclopropyl-hydroxy-methyl)-3-methyl-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-phenylsulfanyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[2-methyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-pyridin-4-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(1-methyl-2-pyridin-4-yl-1H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-phenyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-(2′-methyl-cycloproane))]-[1,2,3]triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-morpholin-4-yl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-[spiro(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl-5-cyclohexane)]-[1,2,3]triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-2-methylsulfanyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[3-methyl-2-(2-methyl-propane-2-sulfonyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamideandN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-{4-[3-methyl-2-(1-methyl-cyclopropyl)-3H-imidazol-4-yl]-1,2,3-triazol-1-yl}-benzamide.16. The compound according to claim 10 wherein the compound is chosenfrom3-[4-(1-Cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclohexyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1,5-dimethyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-isopropyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[1-(4-fluoro-phenyl)-5-methyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-{4-[5-(2-dimethylamino-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-methyl-1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-{4-[5-(2-morpholin-4-yl-ethyl)-1-phenyl-1H-pyrazol-4-yl]-1,2,3-triazol-1-yl}-benzamideandN-[3-Methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,2,3-triazol-1-yl]-benzamide.17. The compound according to claim 10 wherein the compound is chosenfrom:3-[4-(2-Benzenesulfonyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-(2-methoxy-5-trifluoromethyl-phenyl)-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-4-methyl-benzamide3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamideN-(5-tert-Butyl-2-methanesulfinyl-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-(4-pyridin-3-yl-imidazol-1-yl)-benzamideN-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-benzamideandN-(5-tert-Butyl-3-methanesulfonylamino-2-methyl-phenyl)-3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzamide.18. A pharmaceutical composition containing a pharmaceutically effectiveamount of a compound according to claim 1 and one or morepharmaceutically acceptable carriers and/or adjuvants.
 19. A method oftreating an oncological disease comprising administering to a patient apharmaceutically effective amount of a compound according to claim 1.20. A method of treating a disease or condition chosen fromosteoarthritis, atherosclerosis, contact dermatitis, bone resorptiondiseases, reperfusion injury, asthma, multiple sclerosis, Guillain-Barresyndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versushost disease, systemic lupus erythematosus, insulin-dependent diabetesmellitus, rheumatoid arthritis, toxic shock syndrome, Alzheimer'sdisease, diabetes, inflammatory bowel diseases, acute and chronic pain,stroke, myocardial infarction alone or following thrombolytic therapy,thermal injury, adult respiratory distress syndrome (ARDS), multipleorgan injury secondary to trauma, acute glomerulonephritis, dermatoseswith acute inflammatory components, acute purulent meningitis, syndromesassociated with hemodialysis, leukopherisis, granulocyte transfusionassociated syndromes, necrotizing entrerocolitis, restenosis followingpercutaneous transluminal coronary angioplasty, traumatic arthritis,sepsis, chronic obstructive pulmonary disease and congestive heartfailure, said method comprising administering to a patient apharmaceutically effective amount of a compound according to claim 1.